bims-tuinly 2026-09-13 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2026–09–13
ten papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Recent Advances in Tumor-Infiltrating Lymphocyte Therapy for Melanoma.
Emerging frontiers in adoptive cell therapies: engineering innovations, current challenges, and manufacturing perspectives.
Phenotypic and functional characterization of tumor-reactive T cells in malignant pleural effusions.
Association of ADAM17 expression with CD4 + and CD8 + tumor-infiltrating lymphocytes in adrenocortical carcinoma and benign adrenal adenoma.
αTIGIT-guided IL-15 mimetics drive potent and safe antitumor immunity by restoring tumor-infiltrating T cells.
Immunotherapy in the critically ill cancer patient: What the intensivist should know.
Association of immune and proliferation gene signatures and stromal tumor-infiltrating lymphocytes with clinical outcomes in patients with stage I triple-negative breast cancer.
Spatiotemporal CD8+ T-Cell Dynamics: Clonal Replacement and Expansion as Determinants of Sustainable Antitumor Response.
Stem-like CD4 T cells in tumors: an emerging framework for antitumor immunity.
An integrated SOX4-driven transcriptional and metabolic program governs tumor-infiltrating regulatory T cells in ovarian cancer.

Curr Treat Options Oncol. 2026 Sep 11. pii: 47. [Epub ahead of print]27(1):

Recent Advances in Tumor-Infiltrating Lymphocyte Therapy for Melanoma.

Huihua Zeng, Wuxuan Mei, Changchun Zeng.

   OPINION STATEMENT: Melanoma is the most aggressive form of skin cancer and remains a leading cause of skin cancer-related mortality. The therapeutic landscape of melanoma has been revolutionized by the advent of immune checkpoint inhibitors (ICIs), resulting in significant improvements in patient survival. Nevertheless, treatment-related toxicities, resistance mechanisms, and disease progression remain major barriers to durable clinical benefit, highlighting an ongoing unmet medical need. Tumor-infiltrating lymphocyte (TIL) therapy has emerged as a clinically active immunotherapeutic strategy for melanoma, particularly in patients with advanced or refractory disease. Continuous advances in biological understanding, manufacturing technologies, and clinical development have further strengthened its therapeutic potential. This review summarizes the biological basis of TIL therapy and outlines the manufacturing process from tumor procurement to lymphodepletion, TIL infusion, and interleukin-2 support. We then review current clinical evidence for conventional TIL products, including lifileucel, TM001, LM103, HS-IT101, and GC101, highlighting their efficacy and safety profiles. Emerging combination strategies integrating immune checkpoint inhibitors, targeted therapies, and oncolytic adenoviruses are also reviewed. In addition, advances in genetically engineered TILs, such as OBX-115, KSQ-001EX, and IOV-4001, are reviewed. Moreover, this review covers recent advances for improving therapeutic outcomes, including safety optimization, product optimization, next-generation engineered TILs, and predictive biomarkers. Challenges and future directions of TIL therapy in melanoma are also discussed. Overall, TIL therapy constitutes a rapidly evolving and clinically potent treatment modality for melanoma.

Keywords:  Adoptive cell therapy (ACT); Biomarkers; Melanoma; Therapy; Tumor-infiltrating lymphocytes (TILs)

DOI:  https://doi.org/10.1007/s11864-026-01413-0
Mol Biol Rep. 2026 Sep 08. pii: 1554. [Epub ahead of print]53(1):

Emerging frontiers in adoptive cell therapies: engineering innovations, current challenges, and manufacturing perspectives.

Mahdieh Sadat Hosseini Nezhad, Sarvenaz Zeighami Gol, Pouya Gharavi, Hossein Javid.

  Immunotherapy through adoptive cell therapy (ACT) has become an effective cancer treatment method, using genetically modified immune cells or immune cells grown outside the body. The ACT methods use chimeric antigen receptor T (CAR-T) cells, with proven results for blood cancers, while tumor-infiltrating lymphocytes (TILs) and T-cell receptor (TCR)-engineered T cells serve as effective methods to fight against solid tumors and intracellular antigens. The current medical field uses natural killer (NK) cell-based therapies because of their natural ability to destroy cells, their lower incidence of graft-versus-host disease, and their capability to generate readily available therapeutic products through allogeneic medical procedures. The clinical utilization of ACTs has been facing multiple obstacles, stemming from antigen diversity, immune system resistance, treatment-related adverse effects, and difficulties in production. The researchers are advancing multiple solutions to resolve current challenges through developing multi-targeted receptor designs and gene-editing technologies, enhanced cell persistence strategies, and scalable manufacturing platforms. The next-generation ACT platforms will achieve improved therapeutic results through a mix of combination therapies, biomarker-driven patient selection, and advanced manufacturing technologies. Emerging areas of biological research demonstrate how adoptive cell therapies can develop into key components of precision cancer immunotherapy. In this review, we discussed the principles, benefits, and challenges of ACT, with a focus on potential solutions to overcome these obstacles.

Keywords:  Adoptive cell therapy; CAR-T cells; Clinical studies; Emerging technologies; Translational research; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1007/s11033-026-12720-y
Cancer Immunol Res. 2026 Sep 11.

Phenotypic and functional characterization of tumor-reactive T cells in malignant pleural effusions.

Noam S Gaiger, Jack Coburn, Mark N Lee, Lin Zhang, Heng-Le Chen, Gavitt A Woodard, Harriet M Kluger, David A Schoenfeld, Benjamin Y Lu.

Adoptive cell therapy using tumor-infiltrating lymphocytes (TIL) is effective for treating advanced melanoma but requires surgical tumor resection. Malignant pleural effusions (MPE) may provide a more accessible source of tumor-reactive T cells. Synchronously collected MPE, lung metastasis, and blood from a patient with metastatic melanoma were analyzed using high-dimensional flow cytometry, and single-cell RNA/T cell receptor (TCR) sequencing. TCR reactivity to autologous tumor was tested in vitro. The proliferative and cytotoxic capacity of ex vivo expanded T cells was assessed in vitro. MPE contained a higher fraction of CD3+ T cells compared with tumor and was enriched for effector CD8+ T cells and effector memory CD4+ T cells. Compared with TIL, MPE T cells exhibited lower features of T cell exhaustion and higher cytotoxicity signatures. The clonal repertoire of MPE and tumor highly overlapped, including 62.2% of predicted neoantigen-specific (NeoTCR) clonotypes. MHC class I-restricted reactivity was functionally confirmed in two of four selected NeoTCR clonotypes. MPE T cells demonstrated higher proliferative capacity under high-dose IL-2 expansion relative to TIL and achieved comparable MHC class I-dependent tumor killing. Overall, MPE contains polyclonal, tumor-reactive T cells with favorable functional features, supporting MPE as an accessible source for TIL therapy.

DOI: https://doi.org/10.1158/2326-6066.CIR-26-0293
Endocrine. 2026 09 09. pii: 291. [Epub ahead of print]91(1):

Association of ADAM17 expression with CD4 + and CD8 + tumor-infiltrating lymphocytes in adrenocortical carcinoma and benign adrenal adenoma.

Mehmet Sözen, Seda Duman Öztürk, Alev Selek, Berrin Çetinarslan, Zeynep Cantürk, Emre Gezer, Sibel Balcı.

   BACKGROUND: Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy. Although immune checkpoint signaling and tumor-infiltrating lymphocytes (TILs) have been implicated in ACC biology, the role of ADAM10 and ADAM17 in the adrenocortical tumor immune microenvironment remains poorly understood. This study aimed to evaluate the expression of ADAM10, ADAM17, PD-L1, CD4, and CD8 in ACC and benign adrenal adenoma (BAA) tissues.
METHODS: This retrospective study included 21 patients with histopathologically confirmed ACC and 39 patients with BAA. Immunohistochemical staining for ADAM10, ADAM17, PD-L1, CD4, and CD8 was performed on formalin-fixed paraffin-embedded tissue samples. ADAM10 and ADAM17 expression were assessed using H-scores, while CD4 + and CD8 + TIL counts were quantified by cell counting. Comparative and correlation analyses were conducted.
RESULTS: ACC tissues exhibited significantly higher CD4 + and CD8 + TIL counts than BAA tissues (p = 0.010 and p = 0.006, respectively). No significant differences were observed between the groups regarding ADAM10, ADAM17, or PD-L1 expression (all p > 0.05). ADAM17 H-scores showed significant positive correlations with both CD4 + and CD8 + TIL counts in ACC and BAA. No significant associations were found between ADAM10, ADAM17, or PD-L1 expression and Ki-67 index, tumor size, or ENSAT stage.
CONCLUSIONS: In this cohort, ACC tissues showed higher CD4 + and CD8 + TIL counts than BAA tissues. Although ADAM10, ADAM17, and PD-L1 expression did not differ significantly between malignant and benign tumors, ADAM17 expression was positively associated with TIL count. These findings warrant further investigation of the potential relationship between ADAM17 and the immune microenvironment of adrenocortical tumors.

Keywords:  ADAM17; Adrenal adenoma; Adrenocortical carcinoma; Immune microenvironment; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1007/s12020-026-04764-8
Cell Mol Immunol. 2026 Sep 11.

αTIGIT-guided IL-15 mimetics drive potent and safe antitumor immunity by restoring tumor-infiltrating T cells.

Xiangming Liu, Nan Li, Yumeng Chen, Zijun Xie, Tao Huang, Shijie Li, Xinxin Wang, Ruiqi Zhang, Xiaohong Yu, Huiqin Meng, Jingya Guo, Yang Liu, Yang-Xin Fu, Zaopeng Yang.

  Cytokines are powerful modulators of antitumor immunity, but their clinical use is limited by structural instability, short half-life, poor drug-like properties, and severe systemic toxicity. Antibody-based cytokine mimetics have recently emerged to activate immune cells in vitro, but whether these mimetics can overcome the shortcomings of cytokines and exert therapeutic efficacy in vivo remains unclear. Here, we engineered bispecific antibody-based IL-15 mimetics using immunized Alpaca-derived phage display coupled with AlphaFold3-assisted structural screening and comparative screening of multiple formats to identify tandem IL-15 mimetics with strong in vitro bioactivity. Importantly, tandem IL-15R agonistic bispecifics, which simultaneously engage IL-15Rβ and γc, clearly demonstrated antitumor activity in vivo. To better target tumor-infiltrating lymphocytes (TILs), we incorporated a high-affinity anti-TIGIT antibody to guide tandem IL-15Rβγ agonists. This tri-antibody design, αTIGIT-αIL-15Rβγ, resulted in a striking improvement in antitumor activity without detectable systemic toxicity even at high doses. Mechanistically, αTIGIT-αIL-15Rβγ enhanced CD8⁺ T effector function and expanded the number of intratumoral stem-like T cells. Our study highlights a strategy to use TIL-targeted cytokine mimetics to overcome the limitations of native cytokines and enable dose pairing with immune checkpoint blockade (ICB), offering a path toward safer and more effective cytokine immunotherapy.

Keywords:  Anti-tumor immunity; IL-15 mimetics; Nanobody agonist; Safe; TIGIT

DOI:  https://doi.org/10.1038/s41423-026-01467-y
Med Intensiva (Engl Ed). 2026 Sep 09. pii: S2173-5727(26)00176-1. [Epub ahead of print] 502518

Immunotherapy in the critically ill cancer patient: What the intensivist should know.

María Verónica Nievas, Alejandra García-Roche, Maricela Jiménez-López, Cándido Díaz-Lagares.

  Immunotherapy has produced a revolution in the treatment of cancer. It involves manipulating the patient's immune system to identify and destroy malignant cells. There has been an explosion in the development of these therapies in recent decades, with the emergence of monoclonal and bispecific antibodies, immune checkpoint inhibitors, and cellular therapies, including T cells modified with a chimeric antigen receptor (CAR-T cells) and tumor-infiltrating lymphocytes (TILs). While these new therapies offer new hope to patients, they have also introduced a new profile of adverse effects, resulting from the action of a hyperactive immune system, such as infusion reactions, autoimmune phenomena, cytokine release syndrome, and neurotoxicity associated with immune effector therapies, as well as capillary leak syndrome.

Keywords:  Allogeneic transplantation; Anticuerpos monoclonales; CAR-T; Critically ill hematological cancer patient; Cytokine release syndrome; Immune checkpoint inhibitors; Immunotherapy; Immunotherapy-associated neurotoxicity; Inhibidores punto de control inmunitario; Inmunoterapia; Monoclonal antibodies; Neurotoxicidad asociada a inmunoterapia; Paciente oncohematológico crítico; Síndrome de liberación de citoquinas; TIL; TILs; Trasplante alogénico

DOI:  https://doi.org/10.1016/j.medine.2026.502518
Eur J Cancer. 2026 Sep 04. pii: S0959-8049(26)00801-4. [Epub ahead of print]247 117020

Association of immune and proliferation gene signatures and stromal tumor-infiltrating lymphocytes with clinical outcomes in patients with stage I triple-negative breast cancer.

Paolo Tarantino, Tianyu Li, Laia Paré Brunet, Esther Sanfeliu, Beyza Koca, Ruby Guo, Marta Ollé-Monge, Olga Martínez-Sáez, Olivia Cunningham, Melissa E Hughes, Ashka Patel, Tari A King, Elizabeth A Mittendorf, Nancy U Lin, Fara Brasó-Maristany, Guillermo Villacampa, Patricia Villagrasa, Nabihah Tayob, Aleix Prat, Sara M Tolaney.

   BACKGROUND: One-third of patients with triple-negative breast cancer (TNBC) are diagnosed with stage I tumors. Biomarkers to stratify prognosis in this setting remain a major unmet need.
METHODS: Tissue samples and clinicopathologic data were retrieved from consecutive patients with stage I TNBC (defined as ER <10% and HER2-negative) who underwent upfront breast surgery and received standard of care adjuvant systemic therapy at Dana-Farber/Brigham Cancer Center between 2016 and 2021. The TNBC-DX assay (Core Immune Gene [CIG] signature, proliferation signature) was applied to tumor tissue, and stromal tumor-infiltrating lymphocytes (sTILs) were centrally reviewed. Both biomarkers were tested for association with clinical outcomes using the Kaplan-Meier method.
RESULTS: A total of 253 patients with stage I TNBC were included. Most tumors were ductal (88.9%) and high-grade (73.1%); 65.2% of patients received adjuvant chemotherapy. With 18 recurrence events observed, the 3-year recurrence-free survival (RFS) in the overall cohort was 95.0% (95% confidence interval [CI]: 92.1% - 98.1%) and the 3-year overall survival was 97.9% (95% CI: 95.9% - 100.0%). No significant differences in RFS were observed by TNBC-DX (n = 117 patients) or sTILs (n = 123 patients) category. However, a 3-year RFS of 100% (95% CI: 100% - 100%) was observed among the 29 patients with the highest CIG score quartile. A favorable prognosis was also observed in patients with high sTILs (>20%), who experienced a 3-year RFS of 97.0% (95% CI: 90% - 100%). Conversely, a high TNBC-DX proliferation score was numerically associated with poor outcomes, with a 3-year RFS of 83% (95% CI: 68% - 100%).
CONCLUSIONS: In this retrospective study, immune and proliferative features showed opposing prognostic trends in stage I TNBC. Their integration may improve risk stratification and warrants further investigation.

Keywords:  Stromal tumor infiltrating lymphocytes (sTILs); TNBC-DX; Triple-negative breast cancer (TNBC)

DOI:  https://doi.org/10.1016/j.ejca.2026.117020
Cancer Sci. 2026 Sep 07.

Spatiotemporal CD8+ T-Cell Dynamics: Clonal Replacement and Expansion as Determinants of Sustainable Antitumor Response.

Satoshi Ueha, Hiroyasu Aoki, Munetomo Takahashi, Shigeyuki Shichino, Kouji Matsushima.

  The clinical success of immune checkpoint inhibitors (ICI) has shifted the paradigm of cancer treatment, yet the fundamental mechanisms governing the long-term sustainability of antitumor T-cell responses remain elusive. Emerging evidence suggests that the efficacy of ICI depends not only on the reinvigoration of pre-existing tumor-infiltrating lymphocytes but also on the continuous mobilization and replacement of T-cell clones from systemic reservoirs. In this review, we propose a "spatiotemporal ecosystem model" of the antitumor T-cell response. We first delineate the spatial dynamics of T-cell clones, where tumor-reactive progenitors primed in the tumor-draining lymph nodes (dLN) circulate through the peripheral blood to replenish the tumor microenvironment (TME). We highlight that TCR avidity emerges as a key determinant of clonal fate; while high-avidity clones provide potent early cytotoxicity, their susceptibility to accelerated terminal exhaustion eventually creates an available niche that allows for the subsequent expansion of intermediate-avidity successor clones. Furthermore, we discuss how single-cell multi-omics integration (transcriptome, TCR repertoire, and epigenome) reveals that clonal fate is functionally encoded in the molecular and metabolic poise of T cells prior to their expansion. Finally, we discuss the potential of monitoring these clonal dynamics through liquid biopsy as a non-invasive window into the resilience of the immune ecosystem, distinguishing responders with sustainable, polyclonal mobilization from non-responders with frustrated, oligoclonal responses. By integrating clonal evolution, metabolic fitness, and inter-organ crosstalk, this ecosystem perspective offers a comprehensive framework for predicting therapeutic outcomes and developing next-generation precision immunotherapies.

Keywords:  TCR avidity; T‐cell clonal dynamics; clonal replacement; clonal spreading; immune checkpoint inhibitors; liquid biopsy; metabolic fitness; single‐cell multi‐omics; tumor microenvironment

DOI:  https://doi.org/10.1111/cas.70531
Front Immunol. 2026 ;17 1853163

Stem-like CD4 T cells in tumors: an emerging framework for antitumor immunity.

Jiaxiang Xu, Yunchao Yang, Jun Zhang, Yue Zhang.

  Recent studies have identified antigen-experienced TCF1+PD-1+ lineage-negative (lin-) CD4 T cells in several tumor types. Strictly, stemness requires durable self-renewal and multipotent output demonstrated at the single-cell level; these criteria have not yet been established for an individual tumor-associated CD4 T cell. Operationally, this review uses "stem-like CD4 T cells" for TCF1+PD-1+ lin- populations that lack canonical terminal TH1, TH2, TH17, and Treg commitment programs and show population-level persistence and multilineage output. Pending single-cell lineage tracing, these populations are best regarded as candidate progenitor-like states. Within the tumor microenvironment, their differentiation trajectory may influence antitumor immunity. Treg-mediated suppression, TGF-β signaling, metabolic stress, and limited IL-12 can restrain effector differentiation, whereas release of these constraints can permit TH1 output, CD8-supporting activity in tumor-draining lymph nodes, and direct MHC class II-restricted antitumor effects in selected models. Direct tumor evidence remains concentrated in a limited set of studies, while infection, autoimmunity, transplantation, and CD8 research provide contextual or cross-lineage support. This review therefore presents stem-like CD4 biology as an emerging framework and distinguishes established observations from working models.

Keywords:  T cell differentiation; T cell stemness; TCF1; cancer immunotherapy; immune checkpoint blockade; stem-like CD4 T cells; tumor immunity; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1853163
Theranostics. 2026 ;16(15): 8611-8632

An integrated SOX4-driven transcriptional and metabolic program governs tumor-infiltrating regulatory T cells in ovarian cancer.

Lei Wu, Ziqi Tao, Yuelu Zhang, Yepeng Mao, Lei Zhang, Lina Yan, Rong Li, Lingfei Zhou, Zhijie Liu, Wenwen Shang, Shuna Liu, Jianfang Lou, Xi Huang, Ting Wang, Fang Wang.

   Background: Regulatory T cells (Tregs) suppress antitumor immunity in ovarian cancer (OC) and are promising targets for immunotherapy. However, the heterogeneity and regulatory mechanisms of tumor-infiltrating Tregs (TI-Tregs) remain poorly defined. Here, we aim to delineate TI-Treg programs to identify potential therapeutic targets.
Methods: CD4⁺CD25⁺CD127⁻ Tregs from OC, adjacent tissues, and peripheral blood were profiled by single-cell RNA sequencing and spatial transcriptomics, with regulatory networks inferred using SCENIC. Functional and mechanistic studies of SOX4 were performed using hypoxic/tumor-conditioned models, CRISPR-Cas9 perturbation, ectopic overexpression, Cut&Tag profiling, and oxidative phosphorylation (OXPHOS) inhibition.
Results: We identified nine transcriptionally distinct Treg subsets, revealing a highly activated and immunosuppressive state among TI-Tregs. These TI-Tregs exhibited strong co-expression of TNFRSF4, TNFRSF9, TNFRSF18, and CTLA4, and their increased intratumoral abundance was independently associated with poorer overall survival. SCENIC analysis identified SOX4 as the top regulon defining TI-Treg identity, with spatial transcriptomics revealing SOX4⁺ Tregs forming an immunoregulatory barrier at tumor margins. This phenotypic identity was robustly induced by the hypoxic microenvironment and TCR stimulation in a well-established murine OC model. Mechanistically, SOX4 transactivated MT1X to promote mitochondrial fitness and OXPHOS. Consistently, Cut&Tag profiling showed reduced chromatin accessibility at OXPHOS-related loci following SOX4 depletion. Furthermore, CRISPR-Cas9-mediated disruption of SOX4 reduced FOXP3 expression and other suppressive markers, whereas SOX4 overexpression enhanced FOXP3 expression in an OXPHOS-dependent manner. Notably, pharmacological inhibition of OXPHOS abolished this effect.
Conclusions: SOX4 is a central regulator of TI-Treg suppressive function and metabolic fitness, representing a promising therapeutic target for OC.

Keywords:  SOX4 transcription factor; ovarian cancer; regulatory T cells; tumor microenvironment

DOI:  https://doi.org/10.7150/thno.131793