bims-tuinly 2026-10-11 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2026–10–11
29 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

The acidic tumor microenvironment in hepatocellular carcinoma: a barrier to adoptive cellular immunotherapy.
Protocol for analyzing tumor-infiltrating bystander CD8+ T cells in mice using adoptive transfer of P14 TCR-transgenic CD8+ T cells.
Abundant CD8+ tumor-infiltrating lymphocytes in glioblastoma harbor distinct exhaustion signatures in potentially reactive subsets.
Why CD4+ T cells matter in adoptive cell therapy for solid cancers.
CD39 on CD8+ Tumour-Infiltrating Lymphocytes: A Paradoxical Marker of Tumour Reactivity and Immunosuppression.
Therapeutic reprogramming of natural killer cells for solid tumors: expanding frontiers into rare and ultra-rare malignancies.
Advances in IL-2-based cancer immunotherapy and the synergistic role of stem-like CD8+ T cells in IL-2 and PD-1 combination therapy.
Extracellular matrix-targeted TNC-scFv armoring enhances CAR T cell persistence and antitumor activity in solid tumors.
Pharmacologic HIF-2α inhibition preserves T cell effector function in clear cell renal cell carcinoma.
A reciprocally masked anti-CD47/IL-2 fusion protein promotes antitumor immunity and limits systemic toxicity.
Mitochondrial dysfunction as a metabolic checkpoint of immunotherapy response in colorectal cancer.
PRMT7 restricts CD8+ T cells expansion via the NF-ΚB pathway.
Targeting IKZF2 with molecular glue degraders for cancer immunotherapy.
Biomarker discrepancies following chimeric antigen receptor T cells: implications in B-cell acute lymphoblastic leukemia.
Immune-Cell Dynamics in the Tumor Microenvironment: Implications for Cancer Therapy.
Knowledge-guided Multimodal Learning for Interpretable Prediction of Pathological Complete Response and Survival in Breast Cancer.
Cancer competition for vitamin B2 creates metabolic checkpoint for T cell ferroptosis.
PRTN3 drives immunosuppression in KRAS-mutant lung adenocarcinoma through proteolytic inactivation of CXCL9.
Intratumoral Granulomas in Hepatocellular Carcinoma: Clinicopathologic Associations, Prognostic Significance, and Diagnostic Pitfalls.
Ex vivo expansion reshapes invariant natural killer T-cell state, function, and therapeutic fitness.
Divergent immune ecosystems in HPV-associated and HPV-independent lower anogenital tract malignancies.
Tumor-infiltrating lymphocytes and Treg cells in canine melanomas: Site-specific prognostic implications.
SUMO2 deletion changes chromatin accessibility and enhances cytotoxic T cell activation and tumor infiltration.
XIAP inhibition augments personalized neoantigen vaccine-driven antitumor immunity in orthotopic hepatocellular carcinoma.
γδ T Cells in Cancer Immunotherapy, 2000-2025: A Bibliometric Analysis and Clinical-Trial Evidence Map.
Impact of adjuvant therapy on melanoma-specific survival in elderly patients with high-risk resected melanoma: a multicenter international retrospective study.
Identification of SARS-CoV-2-specific cytotoxic lymphocytes in cerebrospinal fluid of a patient with cerebral demyelination Post mRNA vaccination.
Author Correction: Natural killer T cells and CD8+ T cells are dispensable for T cell-dependent allergic airway inflammation.
Low-dose radiotherapy as an immunomodulator in cancer: dose-specific mechanisms and hybrid high-dose/low-dose strategies.

Front Immunol. 2026 ;17 1959235

The acidic tumor microenvironment in hepatocellular carcinoma: a barrier to adoptive cellular immunotherapy.

Jingnan Xiong, Guozirui Mou, Taduoji Ze, Xia Li, Hongyun Zhao.

  The metabolic interface between tumor and immune cells is an emerging determinant of immunotherapy resistance, yet its therapeutic exploitation in hepatocellular carcinoma (HCC) remains limited. Adoptive cellular immunotherapies, including NK cell infusion, tumor-infiltrating lymphocytes (TILs), and chimeric antigen receptor T (CAR-T) cells, have transformed hematologic oncology but repeatedly fail to achieve durable responses in HCC. We argue that an underappreciated driver of this resistance is the acidic tumor microenvironment (TME): hypoxia-driven glycolytic reprogramming acidifies the HCC niche through lactate and proton accumulation, lowering extracellular pH (pHe) to approximately 6.5-6.8 (measured 6.66 ± 0.19 in human HCC by CEST MRI), rewiring macrophages, neutrophils, dendritic cells, NK cells, myeloid-derived suppressor cells, and T lymphocytes toward immunosuppressive or exhausted states. Although lactate and tumor acidity have each been reviewed extensively, the specific implications of acidosis for the design and delivery of cell-based therapies remain scattered and unsynthesized, a gap of growing urgency as the first pH-targeting and acidity-armored cellular products enter clinical testing, as summarized in this review. This mini review delineates how the acidic TME is established in HCC, summarizes cell-type-specific mechanisms of acidosis-driven immune dysfunction, and critically evaluates unresolved issues: the incomplete dissociation of acidity- versus lactate-mediated effects, the metabolic double-edged sword of systemic glycolytic blockade, and the gap between preclinical pH modulation and clinical translation. We conclude that ex vivo metabolic preconditioning and acidity-responsive cell engineering, rather than systemic metabolic intervention, offer the most tractable path toward durable cellular immunotherapy in HCC.

Keywords:  CAR-T cells; acidic tumor microenvironment; adoptive cellular immunotherapy; hepatocellular carcinoma; immune evasion; immunometabolism; lactylation; tumor-associated macrophages

DOI:  https://doi.org/10.3389/fimmu.2026.1959235
STAR Protoc. 2026 Oct 06. pii: S2666-1667(26)00539-3. [Epub ahead of print]7(4): 104886

Protocol for analyzing tumor-infiltrating bystander CD8+ T cells in mice using adoptive transfer of P14 TCR-transgenic CD8+ T cells.

Chunyang Xie, Wenwen Xi, Hairu Wang, Lilin Ye, Xiangyu Chen, Yao Lin.

  While tumor-specific CD8+ T cells become functionally exhausted within the tumor microenvironment (TME), virus-specific bystander memory CD8+ T (TBYS) cells are abundant and represent valuable immunotherapy targets. Here, we present a protocol to analyze tumor-infiltrating virus-specific TBYS cells in murine tumor models using P14 CD8+ T cells. We describe steps for monitoring long-term in vivo behavior of P14 TBYS cells and characterizing their differentiation trajectories and functional heterogeneity. For complete details on the use and execution of this protocol, please refer to Lin et al.1.

Keywords:  Cancer; Cell isolation; Flow Cytometry; Immunology; Model Organisms

DOI:  https://doi.org/10.1016/j.xpro.2026.104886
Br J Cancer. 2026 Oct 05.

Abundant CD8+ tumor-infiltrating lymphocytes in glioblastoma harbor distinct exhaustion signatures in potentially reactive subsets.

Takanari Okamoto, Ryo Mizuta, Ayako Demachi-Okamura, Daisuke Muraoka, Yasunori Fukushima, Hiromasa Ishihara, Yujia Sun, Yizheng Wang, Reina Nishida, Eiichi Sasaki, Katsuhiro Masago, Kazuhide Onoguchi, Yuki Tanaka, Yoshiko Yamashita, Richard Stratford, Trevor Clancy, Osamu Muto, Chin Leng Tan, Yoshihiro Otani, Yoshinobu Takahashi, Rui Yamaguchi, Edward W Green, Michael Platten, Isao Date, Shota Tanaka, Naoya Hashimoto, Hirokazu Matsushita.

BACKGROUND: The effectiveness of immunotherapy against glioblastoma (GBM) remains limited, suggesting that antigen-specific tumor-infiltrating lymphocytes (TILs) are rare. This study aimed to identify tumor-specific T cells in GBM as the basis for antigen-specific immunotherapy.
METHODS: Tumor specimens were collected from 56 patients newly diagnosed with IDH-wildtype GBM. In cases showing prominent intratumoral T-cell infiltration, CD3⁺CD8⁺CD4⁻ T cells were sorted for single-cell RNA and T-cell receptor (TCR) sequencing. Integrated analyses were performed using our single-cell dataset from the Aichi Cancer Center (ACC), publicly available GBM TILs datasets (PA), and lung cancer TILs and malignant pleural effusions datasets (LC). Candidate reactive TCRs were identified using an AI-based algorithm.
RESULTS: Unsupervised analysis identified a dominant cluster characterized by the strong expression of exhaustion markers, most prominently LAG3, with high TCR clonality. Moreover, LAG3 and CXCL13 expression levels were significantly higher in the ACC TIL-rich subset than the PA dataset. Finally, a prediction algorithm suggested that our TIL-rich subset harbored a markedly higher proportion of potentially reactive T cells than the PA and LC datasets.
CONCLUSIONS: TILs with marked clonal expansion in certain GBM cases may include potentially reactive T cells with distinct exhaustion features, providing a foundation for the development of antigen-specific and LAG-3-targeted immunotherapies.

DOI: https://doi.org/10.1038/s41416-026-03619-3
Immunooncol Technol. 2026 Dec;32 101615

Why CD4+ T cells matter in adoptive cell therapy for solid cancers.

S Jegatheeson, C Scheffler, M De Bondt, P K Darcy, P J Neeson.

  Cytotoxic CD8+ T cells have been the focus of research efforts to improve the efficacy of anticancer adoptive cell therapies. However, emerging evidence is highlighting the critical role of CD4+ T cells in these treatments, including chimeric antigen receptor-T cells. Although the presence of CD4+ T cells is known to be important for efficacy of cell therapies, the mechanisms by which CD4+ chimeric antigen receptor-T cells exert their beneficial effects remain incompletely understood. In this article, we review the roles of CD4+ T cells in adoptive cell therapy, highlighting understudied areas that are yet to be explored, and propose new directions to advance our understanding of their antitumour potential.

Keywords:  CD4+ T cells; T cell receptor; adoptive therapy; chimeric antigen receptor T cells; solid cancers; tumor infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.iotech.2026.101615
Eur J Immunol. 2026 Oct;56(10): e70288

CD39 on CD8+ Tumour-Infiltrating Lymphocytes: A Paradoxical Marker of Tumour Reactivity and Immunosuppression.

Manolo Sambucci, Daniela Fenoglio, Francesca Ferrera, Laura Camporesi, Andrea Lagazio, Giovanna Borsellino, Luca Battistini, Gilberto Filaci.

  CD39 (ENTPD1) occupies a paradoxical position in the immunology of solid tumours. On CD8+ tumour-infiltrating lymphocytes (TILs), its surface expression serves as one of the most reliable available markers of genuine tumour-antigen experience and identifies the clonally expanded tissue-resident and cytolytically competent T cells, that are largely absent from the bystander populations, which are specific for tumour-unrelated antigens and numerically dominate many tumour infiltrates. Yet the same enzymatic activity that defines CD39, the hydrolysis of extracellular ATP (eATP) to AMP, directly feeds CD73-dependent adenosine generation. These very cells therefore actively perpetuate the immunosuppressive purinergic milieu that constrains their own effector function and that of surrounding immune cells. CD39+CD8+ TILs thus represent simultaneously the best cellular evidence that a productive anti-tumour immune response has occurred, and among the most potent local drivers of its suppression. This review places this paradox at its centre, dissecting the molecular basis of CD39 expression, its two opposing functional identities across solid tumour types and the therapeutic logic that follows: Blocking CD39 activity could simultaneously release the suppressive brake and preserve the tumour-reactive cells that express it.

Keywords:  CD39; CD8+ TILs; T‐cell exhaustion; adenosine; immune checkpoint blockade; tumour microenvironment; tumour reactivity

DOI:  https://doi.org/10.1002/eji.70288
Front Mol Biosci. 2026 ;13 1955532

Therapeutic reprogramming of natural killer cells for solid tumors: expanding frontiers into rare and ultra-rare malignancies.

Francesca Rosato, James W Hodge.

  Rare and ultra-rare solid tumors collectively account for approximately one-quarter of all cancer diagnoses yet remain associated with poor clinical outcomes. Delayed diagnosis, limited biological characterization, few therapeutic options, and the logistical challenges of conducting adequately powered clinical trials underscore the potential for adaptable cellular immunotherapies that can be applied across diverse tumor histologies. Natural killer (NK) cells have emerged as a promising platform for adoptive cell therapy because of their ability to recognize and eliminate malignant cells independently of major histocompatibility complex restriction, their favorable safety profile, and their suitability for standardized allogeneic, off-the-shelf manufacturing. This review examines the progression of NK cell-based therapies from their biological and therapeutic foundations in solid tumors to their emerging application in rare and ultra-rare malignancies. Recent advances in NK cell engineering are enabling multifunctional cell products designed to enhance tumor recognition, trafficking, persistence, and resistance to the immunosuppressive tumor microenvironment. We also review emerging clinical evidence demonstrating the feasibility and safety of these approaches while highlighting the major biological and translational barriers that continue to limit durable responses. Building on these advances, attention is given to the unique challenges of rare and ultra-rare cancers, where small patient populations, tumor heterogeneity, limited therapeutic targets, and logistical constraints pose unique challenges to conventional drug and cellular therapy development. Finally, we discuss how scalable off-the-shelf manufacturing, rational combination strategies, innovative clinical trial designs, and next-generation technologies, including multiplex gene editing, armored NK cells, and in vivo engineering, may facilitate this translation. Collectively, progress in NK cell therapy across solid tumors provides a framework for extending increasingly adaptable and scalable immunotherapeutic platforms to rare and ultra-rare malignancies, with the potential to expand treatment opportunities for patient populations that have historically had limited therapeutic options.

Keywords:  adoptive cell therapy; chimeric antigen receptor; clinical trials; immunotherapy; natural killer cells; rare tumors; solid tumors

DOI:  https://doi.org/10.3389/fmolb.2026.1955532
Front Immunol. 2026 ;17 1756987

Advances in IL-2-based cancer immunotherapy and the synergistic role of stem-like CD8+ T cells in IL-2 and PD-1 combination therapy.

Huiquan Gao, Shubo Wang, Huiru Yuan, Bingxiu Zhou, Fuxin Zhou.

  IL-2 is a pleiotropic cytokine that plays a central role in the activation and proliferation of cytotoxic lymphocytes and regulatory T cells. Since its discovery in 1976 as a T-cell growth factor and its subsequent U.S. FDA approval for metastatic renal cell carcinoma and melanoma, IL-2 has represented a landmark in cancer immunotherapy. However, high-dose (HD) IL-2 therapy is associated with substantial toxicities, including vascular leak syndrome. Recent advances in structural and receptor biology have clarified the molecular mechanisms underlying IL-2's dual immunostimulatory and immunoregulatory effects. These discoveries have enabled the design of next-generation IL-2 variants (IL-2v) with improved pharmacokinetics, receptor selectivity, and safety profiles. Importantly, PD-1+ TCF-1+ stem-like CD8+ T cells have recently been identified as a key population sustaining long-term antitumor immunity. TCF-1 is a transcription factor associated with a less differentiated, self-renewing state and marks this progenitor-exhausted subset. By contrast, terminally exhausted T cells exhibit a highly differentiated, poorly proliferative state and limited capacity for functional reinvigoration, whereas progenitor-exhausted cells retain stem-like properties, self-renewal capacity, and responsiveness to therapy. Furthermore, these cells respond robustly to IL-2 and are central mediators of the synergy observed between IL-2 signaling and PD-1 blockade. Mechanistically, PD-1 inhibition releases inhibitory constraints, while IL-2 provides a potent STAT5-driven proliferative and differentiation signal that expands the stem-like CD8+ T-cell pool and generates functional effector CD8+ T cells. This review summarizes IL-2 biology, the limitations of high-dose IL-2 (HD IL-2) therapy, and emerging strategies, including CD25- or CD122-biased IL-2 variants, tumor-targeted IL-2 prodrugs, and IL-2-based combination therapies designed to harness IL-2's antitumor potential while minimizing systemic toxicity, with particular emphasis on the role of stem-like CD8+ T cells as key mediators of therapeutic efficacy.

Keywords:  CD122 bias; CD25 bias; IL–2; IL–2 variants; cancer immunotherapy; cytokine engineering; immunocytokines; prodrugs of IL–2

DOI:  https://doi.org/10.3389/fimmu.2026.1756987
Sci Adv. 2026 Oct 09. 12(41): eaeh3957

Extracellular matrix-targeted TNC-scFv armoring enhances CAR T cell persistence and antitumor activity in solid tumors.

Kaizhao Chen, Qi Fu, Wei Zhang, Ziyang Lin, Longjun Chen, Youxi Zhou, Yongkun Huo, Ziqing Gao, Haoyang Wan, Caifang Wang, Xingxu Huang, Shuaishuai Zhang, Ming Liu, Xiaodong Ma.

Chimeric antigen receptor T cell (CAR T cell) therapy has shown limited efficacy in solid tumors, largely due to physical and immunosuppressive barriers imposed by the tumor microenvironment (TME). Tenascin-C (TNC), an extracellular matrix protein highly expressed in multiple solid malignancies, contributes to immune exclusion and T cell dysfunction. Here, we engineer an armored CAR T cell platform that locally targets the extracellular matrix by secreting a TNC-specific single-chain variable fragment (TNC-scFv) linked to conventional CAR architecture. TNC-scFv-armored CAR T cells exhibit enhanced cytotoxic activity, improved persistence, and reduced exhaustion in vitro and in xenograft tumor models. Single-cell transcriptomic analysis reveals that TNC targeting reprograms the TME toward a CD8+ T cell-enriched and functionally active immune landscape. In humanized tumor models, TNC-scFv-armored CAR T cells mediate robust antitumor responses with minimal systemic toxicity. This extracellular matrix-targeted armoring framework is compatible with additional immunomodulatory payloads, as illustrated by combinatorial armoring with interleukin-2, which further enhances efficacy while mitigating cytokine-associated toxicity. Together, these results establish extracellular matrix-directed armoring as a generalizable strategy to improve CAR T cell therapy for solid tumors.

DOI: https://doi.org/10.1126/sciadv.aeh3957
J Clin Invest. 2026 Oct 06. pii: e204613. [Epub ahead of print]

Pharmacologic HIF-2α inhibition preserves T cell effector function in clear cell renal cell carcinoma.

Katrine N Madsen, Soki Kashima, Hanna Soulati, Lena Wirth, Katsuhiro Ito, Zachary A Yochum, Vivien Moritz, Julia Walker, Marc Machaalani, Fady Ghali, Patrick Kenney, Adebowale Adeniran, Michael Hurwitz, Toni K Choueiri, David A Braun.

  Hypoxia-inducible factor 2α (HIF-2α) is a central oncogenic driver in clear cell renal cell carcinoma (ccRCC) and a therapeutic target of the small-molecule inhibitor belzutifan. Genetic studies in murine models have suggested that hypoxia signaling may support T cell effector programs, raising concern that HIF-2α inhibition could impair antitumor immunity. However, whether pharmacologic HIF-2α inhibition alters human T cell biology remains unknown. Here, we investigated the cell-intrinsic effects of EPAS1 (encoding HIF-2α) perturbation in primary human T cells. CRISPR/Cas9-mediated deletion of HIF-2α demonstrated no notable transcriptional effects. Similarly, pharmacologic treatment with belzutifan produced minimal transcriptional changes and did not impair proliferation, cytokine production, polyfunctionality, or cytotoxic activity in T cells derived from healthy donor peripheral blood, peripheral blood from patients with ccRCC, or tumor-infiltrating lymphocytes under hypoxic conditions. High- dimensional immunophenotyping revealed preserved T cell differentiation and activation states following pharmacologic HIF-2α inhibition in vitro and in peripheral blood from patients receiving HIF-2α inhibitor therapy. Together, these findings demonstrate that pharmacologic HIF-2α inhibition preserves key effector programs, providing a mechanistic basis for the immunologic safety of HIF-2α-targeted therapy in ccRCC.

Keywords:  Cancer; Hypoxia; Immunology; Oncology; T cells

DOI:  https://doi.org/10.1172/JCI204613
Cancer Immunol Res. 2026 Oct 05.

A reciprocally masked anti-CD47/IL-2 fusion protein promotes antitumor immunity and limits systemic toxicity.

Elise Léchine, Laura Cons, Laure Garnier, Pauline Malinge, Valéry Moine, Juan C Osorio, Limin Shang, Nicolas Fischer, Stéphanie Hugues, Christoph Scheiermann, Walter Ferlin.

Cancer immunotherapies have achieved meaningful clinical benefit but remain limited by systemic toxicities that restrict the use of potent immune modulators. CD47-targeting antibodies promote tumor cell phagocytosis but are hindered by hematologic toxicity, while IL-2 activates cytotoxic lymphocytes but induces broad, dose-limiting immune activation. Here, we engineered a reciprocally masked antibody-cytokine fusion (aCD47/IL-2c) designed for tumor-selective activation. In this construct, a CD47-specific antibody (aCD47) and an IL-2/IL-2 receptor complex (IL2c) sterically and functionally suppress each other via protease-cleavable linkers, preventing CD47 blockade and IL-2 receptor engagement in circulation while enabling protease-dependent unmasking within the tumor microenvironment. A human construct demonstrated masking and protease-dependent restoration of both CD47-SIRPα blockade and IL-2 signaling, with improved systemic tolerability in human hCD47/hSIRPα transgenic mice, supporting translational potential. A murine analog enabled mechanistic and efficacy studies in immunocompetent tumor models. The tolerability of mouse aCD47/IL-2c was improved in comparison to individual components. Antitumor activity required both CD47 blockade and IL-2 activity, and resulted in a robust antitumor efficacy, including in an immune checkpoint-resistant melanoma model. The robust antitumor efficacy was associated with inflammatory macrophage polarization and increased numbers of effector CD8⁺ T cells inside the tumor. Unlike conventional CD47 antibodies or IL-2 therapies, this approach enabled coordinated, tumor-localized activation of innate and adaptive immunity while limiting systemic exposure. Together, these data highlight reciprocal masking as a clinically relevant strategy to expand the therapeutic index of immune modulators constrained by systemic toxicity.

DOI: https://doi.org/10.1158/2326-6066.CIR-26-0459
Front Immunol. 2026 ;17 1908222

Mitochondrial dysfunction as a metabolic checkpoint of immunotherapy response in colorectal cancer.

Lorenzo Tomassini, Marco Colella, Giovanni Monteleone, Carmine Stolfi, Federica Laudisi.

  Immunotherapy has markedly improved outcomes across multiple cancer types; however, colorectal cancer (CRC) remains largely refractory, with meaningful responses mostly restricted to tumors harboring deficient mismatch repair and high microsatellite instability (dMMR/MSI-H), which represent only a small fraction of CRC cases. Emerging evidence suggests that mitochondrial dysfunction may be viewed as a metabolic checkpoint, representing a conceptual framework through which mitochondrial-dependent processes regulate antitumor immunity and immunotherapy response in CRC. In tumor cells, mitochondrial reprogramming enhances reliance on oxidative phosphorylation, promotes hypoxia, and drives metabolite accumulation, collectively shaping an immunosuppressive tumor microenvironment. In parallel, tumor-infiltrating T-cells exhibit mitochondrial dysfunction characterized by impaired biogenesis, reduced respiratory capacity and features of exhaustion, thereby limiting the efficacy of immune checkpoint inhibitors (ICIs). In this review, we summarize current insights into the role of mitochondrial pathways in regulating tumor immune escape and T-cell dysfunction in CRC. We further discuss emerging therapeutic strategies aimed at targeting metabolic vulnerabilities to overcome resistance and potentially enhance responses to immunotherapy.

Keywords:  T-cell exhaustion; cancer immunotherapy; colorectal cancer; immune checkpoint inhibitors; immune evasion; metabolic reprogramming; mitochondrial dysfunction; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1908222
Nat Commun. 2026 09 06. pii: 10564. [Epub ahead of print]17(1):

PRMT7 restricts CD8+ T cells expansion via the NF-ΚB pathway.

Nivine Srour, Kaixiu Luo, David Allard, Yan Xiong, Zhenbao Yu, Theodore Papadopoulos, François Santinon, Cheng-Hsun Hsieh, Anthony Parent, John Stagg, Simon Turcotte, Dalia Barsyte-Lovejoy, Stéphanie Lehoux, Sonia V Del Rincón, Jian Jin, Stéphane Richard.

Successful cellular immunotherapy for cancer utilising cytotoxic T lymphocytes (CTL) requires efficient expansion while maintaining effector function. Understanding how CTL expansion and function are regulated during the cell preparation process is thus important. Here, we show that T cell-specific deletion of Prmt7 using CD4-Cre increases CD8+ T cell effector differentiation, cytokine secretion, cytolytic activity and anti-tumor responses. Prmt7 deficiency transcriptionally reprograms CD8+ T cells by activating the NF-κB pathway, boosting proliferation, and facilitating the production of effector molecules such as CD25, CD69 and IFNγ. Mechanistically, PRMT7 associates with RelA and restricts RelA nuclear translocation. In vitro, a self-developed PRMT7-targeting PROTAC degrader, MS54, similarly activates the NF-κB pathway as in Prmt7-deficient CTL. In vivo, adoptive cell transfer of MS54-treated OT-I CTLs improves tumor control in a mouse syngeneic melanoma model. In human CTL, MS54 enhances proliferation, activation markers (CD69, CD137) expression, IFNγ production and cytotoxicity toward melanoma. Our findings thus identify PRMT7 as a negative regulator of CD8+ T cell immunity and highlight MS54 as a potential strategy to improve adoptive T cell therapy.

DOI: https://doi.org/10.1038/s41467-026-77155-2
Drug Discov Today. 2026 Oct 05. pii: S1359-6446(26)00225-4. [Epub ahead of print] 104820

Targeting IKZF2 with molecular glue degraders for cancer immunotherapy.

Yaoguang Huang, Shuoqi Huang, Wenwu Liu.

  Regulatory T cells (Tregs) restrain antitumor immunity and limit responses to immune checkpoint blockade (ICB). IKZF2 (Helios), a zinc-finger transcription factor enriched in Tregs, sustains suppressive programs under inflammatory conditions. Therefore, selective IKZF2 degradation has emerged as a strategy to reprogram intratumoral Tregs and enhance antitumor immunity. In this review, we summarize the biological rationale for IKZF2 targeting, the structural basis of cereblon (CRBN)-mediated IKZF2 recruitment and medicinal chemistry principles for improving neosubstrate selectivity. We highlight how degron recognition, CRBN surface remodelling and ternary-complex geometry shape potency, selectivity, off-target liability and translational opportunities for rational immunotherapy combinations.

Keywords:  IKZF2; cancer immunotherapy; molecular glue degrader; regulatory T cells; targeted protein degradation

DOI:  https://doi.org/10.1016/j.drudis.2026.104820
Haematologica. 2026 Oct 08.

Biomarker discrepancies following chimeric antigen receptor T cells: implications in B-cell acute lymphoblastic leukemia.

Chelsea Lamplugh, Julie Ma, Bonnie Yates, Hao-Wei Wang, Constance M Yuan, Chloe Hoang, Sara K Silbert, Tanvi Verma, David Peske, Benjamin L Green, Ilan Kirsch, Challice Bonifant, Nirali N Shah.

Not available.

DOI: https://doi.org/10.3324/haematol.2026.301688
MedComm (2020). 2026 Oct;7(10): e71040

Immune-Cell Dynamics in the Tumor Microenvironment: Implications for Cancer Therapy.

Pin Guo, Yizhao Xie, Rui Song, Mengdi Yang, Zhen Lin, Chao Guan, Zechen Wang, Jin Wen, Guang-Liang Chen.

  Immune-cell dynamics within the tumor microenvironment (TME) determine whether immune cells can reach, recognize, and sustain antitumor function against malignant cells under suppressive pressure. These dynamics are shaped by hypoxia, nutrient stress, cytokine and chemokine signaling, stromal architecture, vascular access, and multicellular crosstalk, and are further regulated by transcriptional and epigenetic programs. In this review, we organize TME immunity around four major barriers to effective therapy: failed immune access, defective antigen visibility and priming, failure to sustain effector function, and suppressive tissue remodeling. We use FOSL2/Fra-2, a component of activator protein-1 (AP-1) transcription factor complexes, as an example of how local signals can produce distinct regulatory effects in malignant, immune, and stromal compartments. FOSL2-associated programs have been linked to differentiation, plasticity, myeloid and stromal remodeling, stress adaptation, and selected immune-regulatory processes; however, the strength and direction of these associations vary by lineage, tumor type, model system, and level of functional evidence. We distinguish perturbation-supported mechanisms from correlative state signatures and identify the need for spatial validation, functional perturbation, and biomarker validation. This perspective supports biomarker-guided TME-directed therapy matched to the dominant immune barrier.

Keywords:  Fos‐like antigen 2; activator protein‐1; cancer immunotherapy; immune‐cell dynamics; transcriptional regulation; tumor microenvironment

DOI:  https://doi.org/10.1002/mco2.71040
Lab Invest. 2026 Oct 09. pii: S0023-6837(26)00099-1. [Epub ahead of print] 106169

Knowledge-guided Multimodal Learning for Interpretable Prediction of Pathological Complete Response and Survival in Breast Cancer.

Wenchuan Zhang, Shuwan Zhang, Yani Wei, Yuanyuan Zhao, Wei Yuan, Xiaoyan Wu, Xunxi Lu, Ting Yin, Libo Yang, Yuhao Yi, Huijuan Shi, Qingjie Lv, Fengling Li, Hong Bu.

   PURPOSE: Pretreatment estimation of pathological complete response (pCR) to neoadjuvant chemotherapy may support risk stratification and future response-adapted clinical studies in breast cancer. However, existing deep learning approaches often rely on "black-box" visual pattern recognition, suffering from poor interpretability, high data dependency, and limited generalizability across heterogeneous cohorts. Here, we present CLASP (Clinical Language-Aligned Slide Pathology), a knowledge-driven, multimodal framework that synergizes pathological expert knowledge with vision-language foundation models.
MATERIALS AND METHODS: CLASP integrates whole slide image (WSI) features encoded by CONCH, patient-specific clinical data, and 16 hierarchical pathological text priors generated by an ensemble of Large Language Models. Through a novel vision-language feature aggregation module and a multi-task consistency constraint, the model aligns visual biomarkers with semantic concepts to jointly predict pCR and prognosis.
RESULTS: Validated on 1,486 patients from four independent cohorts across multiple medical centers, CLASP achieved strong discriminative performance, yielding an Area Under the Curve (AUC) of 0.881 in internal testing and maintaining robustness in external validation (AUC 0.875 and 0.845), with higher AUC point estimates than the 11 evaluated baseline methods. Notably, CLASP also showed improved data efficiency, achieving competitive performance with as few as 8 training samples (few-shot learning). Interpretability analyses suggested that model-highlighted regions were consistent with recognized pathological features associated with treatment response, such as tumor-infiltrating lymphocytes and stromal architecture.
CONCLUSIONS: These findings suggest that pathology-informed multimodal learning may provide a candidate framework for pretreatment risk stratification.

Keywords:  breast cancer; computational pathology; large language models; pathological complete response; survival analysis; vision-language models

DOI:  https://doi.org/10.1016/j.labinv.2026.106169
Cell. 2026 Oct 06. pii: S0092-8674(26)01122-0. [Epub ahead of print]

Cancer competition for vitamin B2 creates metabolic checkpoint for T cell ferroptosis.

Huanpeng Chen, Chao Li, Yujing Ke, Zilong Wu, Ziwei Ou, Nanqi Huang, Zhenyu Lin, Huixin Gao, Xuehu Xu, Lijuan Lu, Zhaofeng Huang, Yingjie Bian.

  Metabolic competition between tumors and T cells drives immune evasion, but the transporters and mechanisms remain largely elusive. Here, we establish the CareSLCs platform and identify that SLC52A3-mediated vitamin B2 (VB2) uptake is indispensable for T cell antitumor immunity. Mechanistically, VB2 deficiency impairs mitochondrial respiration and glutathione regeneration, leading to mitophagy, labile iron accumulation, and lipid peroxidation that trigger T cell ferroptosis. Unexpectedly, tumors preferentially employ SLC52A2, not SLC52A3, to scavenge VB2 and outcompete T cells. Tumor SLC52A2 ablation enhances T cell function in immunocompetent hosts without appreciably affecting intrinsic tumor growth. Clinically, high tumoral SLC52A2 correlates with T cell dysfunction and poor survival, whereas dietary VB2 intake is associated with reduced cancer risks. Thus, VB2 supplementation or SLC52A3 overexpression augments CAR-T cell antitumor efficacy. Our results suggest that tumoral VB2 competition establishes a metabolic checkpoint driving T cell ferroptosis and that enhancing VB2 uptake reinvigorates T cells to improve cancer immunotherapy.

Keywords:  CAR-T cell therapy; SLC52A2; SLC52A3; ferroptosis; metabolic competition; vitamin B2

DOI:  https://doi.org/10.1016/j.cell.2026.09.020
J Immunother Cancer. 2026 Oct 05. pii: e015399. [Epub ahead of print]14(10):

PRTN3 drives immunosuppression in KRAS-mutant lung adenocarcinoma through proteolytic inactivation of CXCL9.

Yi Liu, Chen Zhang, Jia Li, Chong Chen, Song Xu, Tong Li, Huilin Chen, Yigong Hou, Jiayu Jiang, Haojie Chen, Wei Wang, Rong Xiang, Renle Du, Yunping Luo.

   BACKGROUND: KRAS-mutant lung adenocarcinoma (LUAD) shows limited benefit from immune checkpoint blockade (ICB), and the mechanisms by which oncogenic KRAS signaling promotes immune resistance remain poorly understood. Here, we sought to identify tumor-intrinsic mediators of KRAS-driven immune evasion and therapeutic resistance in LUAD.
METHODS: Integrated analyses of human LUAD cohorts, genetically engineered mouse models, tumor cell models, and patient-derived organoids were performed to define the role of PRTN3 in immune regulation. PRTN3 regulation and function were investigated using transcriptional analyses, chromatin immunoprecipitation assays, biochemical cleavage assays, and immune cell co-culture systems. The therapeutic effect of PRTN3 inhibition was evaluated using flow cytometric immune profiling, functional immune assays, and syngeneic tumor models.
RESULTS: We identified PRTN3 as a downstream effector of KRAS signaling that promotes immune evasion in LUAD. Mechanistically, KRAS signaling transcriptionally upregulated PRTN3 through c-Myc activation. Secreted PRTN3 directly cleaved and inactivated CXCL9 in the tumor microenvironment, disrupting CXCL9/CXCR3 signaling and impairing the recruitment and activation of cytotoxic CD8+ T cells and natural killer cells. In patients with LUAD, elevated PRTN3 expression was associated with reduced cytotoxic immune signatures and decreased CXCL9 activity. Genetic inhibition of PRTN3 enhanced antitumor immunity and improved responses to anti-programmed cell death protein 1 therapy in vivo. Furthermore, a hydrolysis-resistant CXCL9 variant restored cytotoxic lymphocyte activation and enhanced immune-mediated tumor cell killing in patient-derived organoids.
CONCLUSIONS: Our findings reveal a KRAS/c-Myc/PRTN3 axis that promotes immune suppression through extracellular proteolytic inactivation of CXCL9. Targeting PRTN3-mediated immune evasion may represent a promising strategy to enhance ICB efficacy in KRAS-driven LUAD.

Keywords:  Cytokine; Immunosuppression; Lung Cancer; T cell; Tumor microenvironment - TME

DOI:  https://doi.org/10.1136/jitc-2026-015399
Hum Pathol. 2026 Oct 07. pii: S0046-8177(26)00244-3. [Epub ahead of print] 106275

Intratumoral Granulomas in Hepatocellular Carcinoma: Clinicopathologic Associations, Prognostic Significance, and Diagnostic Pitfalls.

Jingjing Jiao, Xuchen Zhang.

  Intratumoral granulomas (ITGs) are rarely described in hepatocellular carcinoma (HCC) and may obscure malignancy in limited biopsy specimens. We retrospectively reviewed 614 HCCs diagnosed from 2010 to 2023 to identify tumors with ITG and compared clinicopathologic features and overall survival with HCCs lacking ITG. ITG was identified in 32/614 cases (5.2%). All granulomas were non-necrotizing; 3/32 cases also had granulomas in background liver. No patient had sarcoidosis, primary biliary cholangitis, or documented infection. Patients with ITG were predominantly male (23/32, 71.9%), with a mean age of 67.5 years. Metabolic dysfunction-associated steatotic liver disease (MASLD) was the most common underlying liver disease (13/32, 40.6%). Compared with HCCs without ITG, HCCs with ITG were significantly associated with MASLD (13/32, 40.6% vs 98/582, 16.8%; P = 0.0072), steatohepatitic subtype (22/32, 68.8% vs 119/576, 20.7%; P < 0.0001), intratumoral lymphocytic inflammation (26/28, 92.9% vs 366/572, 64.0%; P = 0.0001), and at least moderate peritumoral inflammation (11/18, 61.1% vs 60/255, 23.5%; P = 0.003). Granuloma-associated inflammation was T-cell predominant and enriched for CD4-positive T cells. In univariable analysis, patients with ITG had improved overall survival (P = 0.004); however, the association was attenuated and did not reach statistical significance after adjustment for age, tumor size, stage, and MASLD etiology (HR 0.52, 95% CI 0.20-1.11; P = 0.098). Among stage II tumors, patients with ITG had borderline improved survival (P = 0.05). Prominent ITG may mask HCC in biopsy specimens. These findings support ITG as an uncommon but recognizable HCC-associated tumor microenvironment enriched in MASLD-related steatohepatitic HCC.

Keywords:  Granuloma; diagnostic pitfall; hepatocellular carcinoma; metabolic dysfunction-associated steatotic liver disease; prognosis; steatohepatitic subtype; tumor microenvironment

DOI:  https://doi.org/10.1016/j.humpath.2026.106275
Clin Immunol. 2026 Oct 06. pii: S1521-6616(26)00121-X. [Epub ahead of print]288 110783

Ex vivo expansion reshapes invariant natural killer T-cell state, function, and therapeutic fitness.

Naeimeh Tavakolinia.

  Invariant natural killer T cells are uniquely positioned at the interface of innate and adaptive immunity, combining CD1d-restricted antigen recognition with rapid, diverse cytokine responses and relatively low HLA-driven alloreactivity. These properties make them attractive candidates for adoptive cellular immunotherapy, yet clinical translation has remained limited by inconsistent potency and persistence. This review considers ex vivo expansion as a determinant of product state rather than a passive scale-up step. Cytokine support, antigen and co-stimulatory signals, restimulation schedule, and culture duration can alter iNKT cell subset composition, survival, phenotype, and effector function, thereby influencing therapeutic fitness. We further discuss how human iNKT cell developmental biology and subset heterogeneity provide a framework for interpreting donor variability and culture-induced drift. We also compare peripheral-blood, hematopoietic stem/progenitor cell (HSPC)-derived, and induced pluripotent stem cell (iPSC)-derived manufacturing platforms and propose critical quality attributes (CQAs) for identity, potency, persistence, survival, and manufacturing safety. Progress will require manufacturing strategies that achieve clinically relevant expansion while preserving a defined and functionally validated cell state.

Keywords:  CAR-iNKT; Ex vivo expansion; Off-the-shelf immunotherapy; iNKT cells; Α-Galactosylceramide

DOI:  https://doi.org/10.1016/j.clim.2026.110783
Front Immunol. 2026 ;17 1937031

Divergent immune ecosystems in HPV-associated and HPV-independent lower anogenital tract malignancies.

Hongmei Wang, Zhifeng Sun, Yanlin Zhang, Hongli Zhu.

  Lower anogenital tract malignancies comprise anatomically adjacent but biologically heterogeneous epithelial cancers of the cervix, vulva, vagina, anal canal and penis. This narrative and conceptual Review used a transparent literature search to examine how human papillomavirus (HPV) etiology intersects with tumor lineage, somatic alterations, antigen-presentation competence, immune-cell state and spatial organization. Evidence quality is heterogeneous: cervical cancer is supported by the largest genomic, single-cell, spatial and randomized-trial literature, whereas vaginal, vulvar and penile cancers remain constrained by small retrospective cohorts and cross-site extrapolation. HPV-associated tumors retain non-self E6/E7 antigens, but viral transcription does not ensure peptide presentation, dendritic-cell priming or epithelial access by functional T cells. HPV-independent tumors lack constitutive viral antigens yet may generate mutation- or differentiation-derived immunity and checkpoint-restrained myeloid-lymphoid niches. We therefore distinguish etiological status from functional immune phenotype and critically appraise three spatial architectures-an inflamed/epithelial-penetrating pattern, a stromally excluded pattern, and an immune-desert pattern-together with an immunosuppressive functional overlay that may occur in any architecture. Clinical evidence is graded separately from mechanistic inference: immune checkpoint blockade has established roles in defined cervical and anal cancer settings, whereas therapeutic vaccines, tumor-infiltrating lymphocytes, T-cell receptor-engineered therapies, myeloid or stromal sensitization and artificial-intelligence-guided selection remain investigational or context dependent. A three-tier biomarker framework is proposed, separating routine clinical assays from extended translational profiling and exploratory single-cell, spatial and artificial-intelligence methods. This framework is hypothesis-generating, not a validated treatment-selection algorithm; assay combinations, thresholds and incremental clinical utility require prospective, multicenter and site-stratified validation.

Keywords:  HPV-independent carcinogenesis; antigen presentation; human papillomavirus; immune checkpoint inhibitor; lower anogenital tract malignancies; precision immunotherapy; spatial transcriptomics; tumor immune microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1937031
Vet Immunol Immunopathol. 2026 Oct 06. pii: S0165-2427(26)00166-2. [Epub ahead of print]301 111226

Tumor-infiltrating lymphocytes and Treg cells in canine melanomas: Site-specific prognostic implications.

Carlos Humberto Costa Vieira-Filho, Emerson Soares Veloso, Jean Nunes Santos, Enio Ferreira, Karine Araujo Damasceno, Ricardo Wagner Portela, Suélen Dias Silva Dos Reis, Raphael Bermal Costa, Gilson Correia Carvalho, Alessandra Estrela-Lima.

  The human melanoma-associated lymphocytic inflammatory infiltrate is considered a prognostic factor; however, this relationship remains poorly established in canine melanomas. Thus, this study aimed to evaluate 117 canine melanomas from different locations (oral cavity/digital - n = 74; cutaneous melanomas - n = 43) using morphological and morphometric analyses of inflammatory cells, CD4 + and FoxP3 + lymphocyte population, and survival rates. Regardless of location, most canine melanomas presented a low frequency of associated inflammatory response. However, when present, the inflammation was discrete, with a focal/multifocal distribution, predominantly lymphocytic, frequent in larger tumors, and associated with higher survival rates. Inflammation was more frequent in oral/digit tumors. Still, it was associated with a milder profile than infiltrates in cutaneous melanomas, with lymphocytes as the predominant cell type and a higher frequency of CD4 + and FoxP3 + cells in more extensive and aggressive tumors. These results indicate that aggressive tumors elicit an immune response, but it is associated with a regulatory profile.

Keywords:  Dogs; Inflammation; Melanocytic tumors; Regulatory cells

DOI:  https://doi.org/10.1016/j.vetimm.2026.111226
Sci Adv. 2026 Oct 09. 12(41): eaef2217

SUMO2 deletion changes chromatin accessibility and enhances cytotoxic T cell activation and tumor infiltration.

Mohottige D Neranjan Tharuka, Dai-Hua Chen, Maria Luisa Jurgensen Amaral, Tianchen Ren, Yixuan Kuang, Shih-Ting Huang, Nikhil Chilakapati, Bing Ren, Stephen P Schoenberger, Ye Zheng, Yuan Chen.

Cytotoxic T cells [cytotoxic lymphocytes (CTLs)] are crucial for adaptive immunity leading to prolonged survival and potential cures for cancer. Recent clinical data have shown that pharmacological inhibition modifies the tumor microenvironment (TME) and activates CTLs, although the mechanism is not well described. In this study, we found that T cell-specific knockout (KO) of the most prevalent SUMO paralog, Sumo2/SUMO2, in both mouse and human CD8+ T cells significantly enhanced CD8+ T cell activation without enhanced IFN-I (type I interferon)-responsive genes in vitro but increased chromatin accessibility at enhancer regions for AP-1 (activating protein 1) family members, including BATF and JunB, which are known to promote T cell activation and proliferation. Using antigen-specific OT1 and CAR (chimeric antigen receptor) T cell models, we found that Sumo2 KO CD8+ T cells had significantly higher tumor infiltration, as revealed by flow cytometry, immunofluorescence staining, and single-nucleus RNA sequencing (snRNA-seq), and conferred greater tumor growth inhibition than wild-type control T cells. snRNA-seq also revealed that Sumo2 KO in CD8+ T cells increased the expression of TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) in vivo and activated the antitumor immune microenvironment, likely through cell-cell interaction involving more activated CTLs. These findings elucidate a novel mechanism by which SUMOylation controls CTL activation and tumor infiltration that activate antitumor immunity in the TME. SUMO2 KO can also be a potential strategy to enhance adoptive T cell therapies for solid tumors by enhancing their activation, tumor infiltration and ability to modulate the TME.

DOI: https://doi.org/10.1126/sciadv.aef2217
J Immunother Cancer. 2026 Oct 09. pii: e014831. [Epub ahead of print]14(10):

XIAP inhibition augments personalized neoantigen vaccine-driven antitumor immunity in orthotopic hepatocellular carcinoma.

Xiaoyuan Zheng, Jun Fu, Geng Chen, Yao Huang, Junjing Huang, Zhenli Li, Wenting Zhong, Bingchen Wu, Ruijing Tang, Yanv Yue, Tingfeng Huang, Lingtian Meng, Pan Mou, Peizhe Chen, Luobin Guo, Xiuqing Dong, Xiaolong Liu, Yongyi Zeng, Zhixiong Cai.



Keywords:  Hepatocellular Carcinoma; Immunotherapy; Vaccine

DOI:  https://doi.org/10.1136/jitc-2026-014831
Crit Rev Oncol Hematol. 2026 Oct 06. pii: S1040-8428(26)00523-8. [Epub ahead of print] 105636

γδ T Cells in Cancer Immunotherapy, 2000-2025: A Bibliometric Analysis and Clinical-Trial Evidence Map.

Yuheng Wang, Yuanzhi He, Jiayu Xu, Yujia Wang, Hengjie Su, Yarong Zhang, Jiadi Lv, Hui Chen, Jing Wang.

  γδ T cells are promising cancer-immunotherapy effectors because they recognize tumors without major histocompatibility complex (MHC) restriction and carry low graft-versus-host-disease risk in allogeneic settings, yet few bibliometric studies have integrated immunotherapy-specific research trends with clinical-trial mapping and translational-gap analysis. We characterized the global research output, intellectual foundations, emerging frontiers, and clinical translation of γδ T cells in cancer immunotherapy (2000-2025) by combining bibliometric analysis of 3,273 Web of Science publications (bibliometrix, VOSviewer, CiteSpace), a Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR)-guided evidence map of 26 interventional cancer trials (ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform [WHO ICTRP], regional registries), and an integrative step linking bibliometric hotspots to the pipeline. Annual output grew from 18 (2000) to 418 (2024) publications (compound annual growth rate [CAGR], 14.0%) across three phases; China (33.1%) and the United States (27.3%) led production. Co-citation analysis identified five intellectual pillars: phosphoantigen recognition, subset heterogeneity, clinical adoptive transfer, tumor-microenvironment suppression, and engineered γδ T therapy. Chimeric antigen receptor-engineered γδ T cells (CAR-γδ T cells), allogeneic platforms, and single-cell RNA sequencing were the leading 2022-2025 frontier terms. Trials shifted toward allogeneic cell sources; early-phase studies consistently met safety and feasibility endpoints, but monotherapy efficacy was modest. The LAVA-051 and LAVA-1207 programs were discontinued for disclosed business or internal-benchmark reasons, whereas allogeneic CAR-Vδ1 therapy (ADI-001) produced the most encouraging early signals before oncology reprioritization in 2024. Three persistent translational gaps-single-cell/T-cell receptor (TCR) profiling, metabolic reprogramming, and γδT17 biology-frame a proposed roadmap to convert bibliometric hotspots into mechanism-guided γδ T-cell cancer immunotherapy.

Keywords:  CAR-γδ T cells; bibliometric analysis; cancer immunotherapy; clinical trials; γδ T cells

DOI:  https://doi.org/10.1016/j.critrevonc.2026.105636
J Immunother Cancer. 2026 Oct 07. pii: e016060. [Epub ahead of print]14(10):

Impact of adjuvant therapy on melanoma-specific survival in elderly patients with high-risk resected melanoma: a multicenter international retrospective study.

Andrea Boutros, Janet McKeown, Roger Olofsson Bagge, Lars Ny, Jan Mattsson, Francesco Spagnolo, Enrica Teresa Tanda, Ralf Gutzmer, Piyush Grover, Lydia Warburton, Muhammad Adnan Khattak, Douglas B Johnson, Kyle P Maas, Hannah Burnette, Ryan J Sullivan, Derek Effiom, Aleigha R Lawless, Paolo A Ascierto, Vito Vanella, Caroline Gaudy-Marqueste, Nausicaa Malissen, Tobias Peres, Anadil Javaid, Praveena Idaikkadar, Celeste Lebbé, Laetitia Da Meda, Hazel Burke, Ines Pires da Silva, Alexander C J van Akkooi, Matteo S Carlino, Serigne N Lo, Georgina V Long, Alexander M Menzies.

   PURPOSE: Adjuvant systemic therapy improves recurrence-free survival in resected high-risk melanoma, but elderly patients remain markedly under-represented in clinical trials; their competing risk of death from other causes needs to be considered. Consequently, the clinical benefit of adjuvant therapy in older populations remains uncertain. We conducted an international real-world study to evaluate survival outcomes of patients aged ≥75 years with resected stage III-IV melanoma managed with adjuvant systemic therapy or observation.
METHODS: In this multicenter retrospective cohort study, patients aged ≥75 years with completely resected stage III-IV cutaneous melanoma were identified across 14 international melanoma centers. Patients received either standard adjuvant systemic therapy (anti-programmed cell death protein 1 immunotherapy or BRAF/MEK-targeted therapy) or observation. The primary endpoint were melanoma-specific survival (MSS) and overall survival (OS). Secondary endpoints included recurrence-free survival (RFS). Survival outcomes were estimated using Kaplan-Meier methods and evaluated with multivariable Cox regression models adjusted for age, stage, sex, and mutation status.
RESULTS: A total of 580 patients were included (median age 79 years; range, 75-99), of whom 222 (38%) received adjuvant therapy and 358 (62%) underwent observation. Adjuvant therapy was associated with significantly improved MSS, with 5-year MSS of 74% compared with 60% in the observation group (adjusted HR 0.58; 95% CI 0.40 to 0.85; p=0.005), as well as OS (adjusted HR 0.66, 95% CI 0.51 to 0.87; p=0.002). Adjuvant therapy was also associated with improved RFS (HR 0.57, 95% CI 0.45 to 0.72; p<0.0001). Among patients managed with observation, disease recurrence occurred in 69%, yet only 47% of those patients received systemic therapy as first-line management of recurrence. Notably, among observation patients who remained recurrence-free or received systemic therapy after recurrence, MSS was comparable to that observed in adjuvant-treated patients (HR 0.83; 95% CI 0.55 to 1.25).
CONCLUSION: In this large international real-world cohort of elderly patients with resected melanoma, adjuvant therapy was associated with clinically meaningful improvements in MSS, OS and RFS. Although immunotherapy retained efficacy when administered at recurrence, many elderly patients did not receive systemic therapy as first-line management of recurrence. Adjuvant therapy may therefore represent an important strategy to ensure timely access to effective treatment in carefully selected older patients.

Keywords:  Adjuvant; Geriatric; Immunotherapy; Melanoma; Survivorship

DOI:  https://doi.org/10.1136/jitc-2026-016060
Front Immunol. 2026 ;17 1920061

Identification of SARS-CoV-2-specific cytotoxic lymphocytes in cerebrospinal fluid of a patient with cerebral demyelination Post mRNA vaccination.

Takaya Kitano, Masakazu Ishikawa, Makoto Kinoshita, Keigo Kihara, Shuhei Sakakibara, Tomohiro Yata, Ryohei Yamamura, Hideki Mochizuki, Masaru Yokoe, Tatsusada Okuno, Daisuke Okuzaki.

   Introduction: Some cerebral demyelinating lesions occur after vaccination. We aimed to elucidate the precise roles of vaccine-activated immune cells and antigen-specific lymphocytes in the central nervous system of a patient who developed cerebral demyelination after vaccination.
Methods: Using comprehensive single-cell RNA sequencing and immune repertoire analysis combined with a lymphocyte stimulation assay, we characterized the immunological landscape of a patient who developed right-hand clumsiness after receiving an mRNA vaccine against SARS-CoV-2 and was subsequently diagnosed with tumefactive cerebral demyelination.
Results: Natural killer cells and effector CD8+ T cells in the cerebrospinal fluid were more cytotoxic and activated than those in healthy controls. Effector CD8+ T cells specific to SARS-CoV-2 spike peptides were identified in the cerebrospinal fluid. The proportion of these cells in peripheral blood decreased after corticosteroid therapy, in parallel with clinical improvement and a reduction in lesion size.
Discussion: Although a direct causal relationship between vaccination and demyelination remains uncertain, our findings suggest that vaccine-activated cytotoxic lymphocytes contribute to immune-mediated demyelinating events in the central nervous system.

Keywords:  T cell; demyelination; multiple sclerosis; natural killer cells; repertoire; single cell; vaccination

DOI:  https://doi.org/10.3389/fimmu.2026.1920061
Nat Med. 2026 Oct 08.

Author Correction: Natural killer T cells and CD8+ T cells are dispensable for T cell-dependent allergic airway inflammation.

Jyoti Das, Paul Eynott, Ray Jupp, Alfred Bothwell, Luc Van Kaer, Yufang Shi, Gobardhan Das.

DOI: https://doi.org/10.1038/s41591-026-04709-8
Biomark Res. 2026 Oct 09. pii: 133. [Epub ahead of print]14(1):

Low-dose radiotherapy as an immunomodulator in cancer: dose-specific mechanisms and hybrid high-dose/low-dose strategies.

Jingjing Deng, Demiao Kong, Wentao Wang, Qikun Mao, Xun Zhao, Limin Ye, Dejun Cui, Qian Long, Chuan Xu, Liankui Han, Jianfeng Zhou, Lin Yang.

  Low-dose radiotherapy (LDRT), conventionally defined as fractional doses of approximately 0.5-2 Gy, has attracted increasing interest as an immunomodulatory rather than a primarily cytoreductive use of ionizing radiation. Many of the immune mechanisms attributed to LDRT-immunogenic cell death (ICD), activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, antigen release, and remodeling of the tumor immune microenvironment (TIME)-occur across a wide range of radiation doses and are therefore not exclusive to the low-dose setting. This review is organized around that distinction: For each mechanism, we separate effects shared with radiotherapy in general from those for which dose-specific evidence supports a preferential or qualitatively different response at low doses, including the avoidance of TREX1-mediated degradation of cytosolic DNA that follows single fractions above approximately 12-18 Gy; the relative sparing of tumor-infiltrating lymphocytes; and the reprogramming of vascular, stromal, and myeloid compartments that remain viable after irradiation. We then examine immune cell reprogramming, the current clinical evidence for combining LDRT with immune checkpoint inhibitors (ICIs), and "hybrid" high-dose/low-dose (HDRT-LDRT) regimens, in which ablative doses to selected lesions prime antigen release while low doses to the remaining disease sustain immune cell infiltration. Because most mechanistic data are derived from individual preclinical models, whereas clinical data remain confined to early-phase, largely single-arm studies, we indicate throughout whether a conclusion is established, emerging, or model-specific, and we outline the trials required to define the LDRT dose window, its sequencing with ICIs, and appropriate patient selection.

Keywords:  Hybrid radiotherapy; Immune checkpoint inhibitors; Immunomodulation; Low-dose radiotherapy; Radiation dose–response; Tumor immune microenvironment; cGAS–STING pathway

DOI:  https://doi.org/10.1186/s40364-026-00999-9