bims-tuinly 2026-07-26 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2026–07–26
twenty-one papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Tumor-infiltrating lymphocyte (TIL) therapy: Historical context, clinical applications, and future directions.
IL-2(N88D)/CD25 Fusion Protein Enhances Expansion of Antigen-Specific CD8⁺ T Cells to Suppress Hepatocellular Carcinoma.
Protocol for high-throughput droplet-engineered TIL-retaining tumor organoids in triple-negative breast cancer.
Pretreatment stromal CD4⁺ T-cell density predicts favorable response to total neoadjuvant therapy in locally advanced rectal cancer.
In vitro inhibition of STAT5 signaling limits CD8⁺ T cell exhaustion and improves outcomes in adoptive T-cell therapy.
Reversal of T cell exhaustion enables cancer vaccine efficacy in BRCA1-deficient ovarian cancer.
A novel peptide-MHC-based T cell engager synergizes with tumor-targeted IL-12 for immunotherapy of solid tumors.
Immune checkpoint profiling of B7-H proteins predicts survival and treatment response in metastatic clear cell renal cell carcinoma.
Association between PLVAP downregulation and increased lymphocyte infiltration in newly diagnosed glioblastoma treated with bevacizumab.
Efficient generation of human cDC1-like cells to detect and enhance tumor-reactive T cells via CD4+ T cell help.
Multiomics Analysis Reveals CTHRC1+ CAFs Drive Immunosuppressive Niches and Predict Immunotherapy Resistance in Gastric Cancer.
Parallel 4-1BB Signaling in Dual DLL3/CD56-Targeting CAR-T Cells Triggers Adaptive Proliferation and Functional Persistence to Eradicate Small Cell Lung Cancer.
CAR-T and TIL therapies in solid tumors: barriers, clinical lessons, and convergent solutions.
BAG3+ CAF-T cell neighborhood predicts resistance to neoadjuvant chemoimmunotherapy in NSCLC.
Computational identification of antigen-specific T cell groups through generative epitope modeling.
TCM-derived immunometabolic modulators as systems adjuvants for CAR-T therapy in solid tumors: evidence hierarchy and translational roadmap.
Tertiary lymphoid structures harbour stem-like tumour-specific T cells.
Circulating immune and biochemical markers predict tumor response to immunotherapy in advanced melanoma and lung cancer.
Twenty-year persistence of WT1-specific cytotoxic T lymphocytes in peritumoral brain tissue by peptide vaccine therapy: Transcriptomic evidence for resident memory T-cell induction.
Response to letter Re: "Progression risk among responders to PD-1/PD-L1 blockade is primarily stratified by response depth".
New Therapeutic Cancer Vaccine with Lenalidomide Induces Potent T Cell Immunity and Inhibits HPV E6/E7-Expressing Tumor Growth in Mice.

Cancer. 2026 Aug 01. 132(15): e70526

Tumor-infiltrating lymphocyte (TIL) therapy: Historical context, clinical applications, and future directions.

Shen Li, Alexandra E Rojek, Reid Shaw, Cristina O'Donoghue, J Michael Millis, Daniel J Olson.

  In the past 15 years, immunotherapy has become a major strategy for cancer therapy. Tumor-infiltrating lymphocyte (TIL) therapy has been under investigation for nearly four decades and received its first Food and Drug Administration approval in 2024, when lifileucel was approved for patients with previously treated metastatic melanoma. TIL therapy is a form of cell-based immunotherapy that uses autologous T cells isolated from the tumor microenvironment, which are expanded ex vivo and reinfused to mediate tumor regression after lymphodepleting chemotherapy and high-dose interleukin-2. Current data demonstrate durable responses in a subset of heavily pretreated patients with advanced melanoma, and early clinical studies suggest activity in other immunogenic solid tumors. In this review, the historical development of TIL therapy, its current clinical applications, emerging strategies to optimize product composition and the tumor microenvironment, and the critical role of surgeons in TIL procurement and delivery are summarized.

Keywords:  IL‐2; TILs; adoptive cell therapy

DOI:  https://doi.org/10.1002/cncr.70526
Commun Biol. 2026 Jul 20.

IL-2(N88D)/CD25 Fusion Protein Enhances Expansion of Antigen-Specific CD8⁺ T Cells to Suppress Hepatocellular Carcinoma.

Nan Xu, Yisu Song, Zhaofeng Xiao, Yiyuan Chen, Lijun Meng, Zhengxing Lian, Tianwei Chen, Zhoucheng Wang, Xiao Xu, Hongda Ding, Shuai Wang, Jian Wu.

Hepatocellular carcinoma (HCC) remains a major cause of cancer-related death worldwide, with limited efficacy of current immunotherapies due to an immunosuppressive tumor microenvironment and dysfunctional CD8⁺ tumor-infiltrating lymphocytes (TILs). Among these, PD-1⁺CD25⁺ CD8⁺ T cells represent a tumor-reactive subset linked to IL-2 responsiveness and favorable responses to PD-1 blockade. In this study, we integrated single-cell and spatial transcriptomics with clinical immunotherapy cohort analyses to characterize the phenotype and function of PD-1⁺CD25⁺ CD8⁺ TILs in human HCC. To therapeutically exploit this subset, we engineered IL-2(N88D)/CD25 fusion proteins with trimeric receptor bias, selectively promoting the expansion of PD-1⁺CD25⁺ CD8⁺ T cells. These constructs were tested in multiple murine HCC models, including orthotopic and hydrodynamic tail vein injection systems. PD-1⁺CD25⁺ CD8⁺ TILs were enriched in HCC tumors, particularly in immunotherapy responders, and exhibited enhanced tumor reactivity and neoantigen specificity. Treatment with IL-2/CD25 led to increased CD8⁺ T cell infiltration and delayed tumor progression with minimal toxicity, while the IL-2(N88D)/CD25 variant further boosted infiltration, activation, and survival outcomes. These findings highlight the therapeutic potential of selectively activating antigen-specific CD8⁺ T cells via IL-2(N88D)/CD25 fusion proteins, offering a promising strategy for improving HCC immunotherapy.

DOI: https://doi.org/10.1038/s42003-026-10699-7
STAR Protoc. 2026 Jul 17. pii: S2666-1667(26)00359-X. [Epub ahead of print]7(3): 104706

Protocol for high-throughput droplet-engineered TIL-retaining tumor organoids in triple-negative breast cancer.

Xiaolong Zhou, Yu Zhu, Wanlong Wang, Yongde Cai, Zhiyuan Liu, Yingshi Su, Shaohua Ma.

  Here, we present a protocol for generating high-throughput, droplet-engineered tumor organoids from triple-negative breast cancer (TNBC) tissues using the OrgFab® micro-sphere printing system. We describe tumor dissociation, bioink preparation, and automated organoid fabrication. We further detail rho-associated coiled-coil kinase (ROCK) pathway modulation to preserve tumor-infiltrating lymphocytes (TILs) and enhance T cell function, as well as flow cytometry-based immune characterization (Figure 1). This protocol enables scalable production of immune-competent tumor organoids for immunological analysis and drug-screening applications. For complete details on the use and execution of this protocol, please refer to Zhou et al.1.

Keywords:  Biotechnology and bioengineering; Cancer; Organoids

DOI:  https://doi.org/10.1016/j.xpro.2026.104706
Biomol Biomed. 2026 Jul 17.

Pretreatment stromal CD4⁺ T-cell density predicts favorable response to total neoadjuvant therapy in locally advanced rectal cancer.

Hatice Telci, Sabin Goktas Aydin, Taskın Erkinuresin, Sinan Can Tasan, Enes Ozluk, Emre Bozdag, Fatma Sahin, Erkan Somuncu.

Total neoadjuvant therapy (TNT) has become an important treatment strategy for locally advanced rectal cancer (LARC), increasing the need for pretreatment biomarkers that may predict major tumor response and support organ-preserving approaches. This study aimed to evaluate whether pretreatment stromal CD4⁺ and CD8⁺ T-cell densities, together with stromal tumor-infiltrating lymphocytes (TILs), are associated with response to TNT in patients with LARC. In this retrospective study, 45 patients with LARC who completed TNT were analyzed; pretreatment colonoscopic biopsy specimens were available for all patients, and paired post-treatment resection specimens were available for 40 surgically treated patients. CD4⁺ and CD8⁺ T-cell densities were assessed immunohistochemically in stromal hotspot areas and expressed as cells/mm², while stromal TILs were evaluated on hematoxylin-eosin sections. A favorable response was defined as tumor regression grade (TRG) 0-1 in surgically treated patients or clinical complete response in patients managed with a watch-and-wait strategy. Median pretreatment CD4⁺ T-cell density, CD8⁺ T-cell density, and stromal TIL percentage were 320 cells/mm², 64 cells/mm², and 30%, respectively. Receiver operating characteristic (ROC) analysis identified a pretreatment stromal CD4⁺ T-cell density cutoff of 410 cells/mm² for favorable response, with an area under the curve (AUC) of 0.68 (p=0.041). CD4⁺ T-cell density >410 cells/mm² was significantly associated with favorable response and remained independently associated with response in multivariable logistic regression analysis (odds ratio [OR]=5.05, 95% confidence interval [CI]: 1.21-20.83, p=0.026). In contrast, pretreatment CD8⁺ T-cell density and stromal TIL percentage were not significantly associated with response. In paired specimens, CD8⁺ T-cell density increased significantly after treatment (p<0.001), whereas CD4⁺ T-cell density and stromal TIL percentage did not change significantly. Lymphovascular invasion (LVI) and perineural invasion (PNI) were associated with non-favorable response. High pretreatment stromal CD4⁺ T-cell density may represent a candidate biomarker of favorable response to TNT in LARC, while the post-treatment increase in CD8⁺ T-cell density suggests a potential immunomodulatory effect of TNT; however, prospective validation in larger cohorts is required.

DOI: https://doi.org/10.17305/bb.2026.14270
Cancer Immunol Res. 2026 Jul 22.

In vitro inhibition of STAT5 signaling limits CD8⁺ T cell exhaustion and improves outcomes in adoptive T-cell therapy.

Mitra Shourian, Benoîte Bourdin, Nehme El-Hachem, Clémence Ruisseaux, Alexis Vallée, Arnau Ballestero Vidal, Olivier Gingras, Hugo Roméro, Edward O Kwarteng, Élie Haddad, Vincent-Philippe Lavallée, Jean-Christophe Beltra, Hélène Decaluwe.

T cell exhaustion remains a barrier to adoptive cell therapies. Although γc cytokines are used to expand T cells, their impact on T cell states remains incompletely defined. Using an in vitro model of repetitive TCR stimulation, we found that high-dose IL-2 or IL-15 promoted exhausted CD8⁺ T cell (TEX) differentiation, with increased inhibitory receptor expression and loss of stem-like features. During chronic LCMV Clone 13 infection, high IL2Rβ expression marked virus-specific CD8⁺ T cells with features of terminally exhausted TEX cells, whereas IL2Rβ deficiency favored progenitor-like populations. In TEX cells, IL-2 and IL-15 preferentially induced STAT5 phosphorylation over other signaling pathways. Genetic disruption of STAT5 similarly supported progenitor subsets, implicating STAT5 in the progression toward more differentiated TEX states under chronic stimulation. We therefore asked whether transient STAT5 attenuation during in vitro T cell expansion could bias differentiation toward progenitor-like populations without compromising functional competence. Transient JAK3 or STAT5 inhibition enriched TCF1⁺Ly108⁺ progenitor-like cells while preserving cytokine production and degranulation capacity. Following transfer into tumor-bearing mice, cells expanded under STAT5-inhibited (STAT5i) conditions mediated superior tumor control and prolonged survival. Likewise, transient STAT5 inhibition preserved memory-progenitor phenotypes in human CD22 CAR T cells without impairing cytotoxicity. RNA sequencing of STAT5i-expanded CD8⁺ T cells confirmed reinforced stem-like transcriptional programs and reduced enrichment of effector and exhausted signatures. Together, these findings identify the IL-2Rβ-STAT5 axis as a regulator of CD8⁺ T cell differentiation and support transient STAT5 modulation during ex vivo expansion to improve therapeutic T cell products.

DOI: https://doi.org/10.1158/2326-6066.CIR-25-1493
iScience. 2026 Jul 17. 29(7): 116587

Reversal of T cell exhaustion enables cancer vaccine efficacy in BRCA1-deficient ovarian cancer.

Laurent Beziaud, Aspram Minasyan, Cheryl L-L Chiang, Rania M Soukarieh, Matilde M Coppi, Raphaël Rovelli, Jonathan Thevenet, Stephanie Tissot, Denarda Dangaj-Laniti, Lana E Kandalaft.

  BRCA mutations in ovarian cancer (OC) are associated with increased tumor-infiltrating lymphocytes and inflammatory features, yet immunotherapy for OC has shown limited efficacy. Using the ID8 mouse model, we discovered that Brca1 deficiency-but not Brca2-impairs the effectiveness of a dendritic cell-based cancer vaccine (OCDC). OCDC vaccine reduced tumor growth and improved survival in mice bearing Trp53 -/- and Trp53 -/- Brca2 -/- tumors but was ineffective against Trp53 -/- Brca1 -/- tumors. Transcriptomic analysis revealed metabolic and immunologic reprogramming in OCDC-responsive tumors, whereas Brca1 -/- tumors remained refractory. Vaccine inefficacy was associated with a pre-existing inflamed microenvironment, enriched in activated yet exhausted T cells, limiting further immune stimulation by vaccination. Combining OCDC with anti-VEGF and PARP inhibitors partially restored vaccine efficacy in Brca1 -/- tumors, while addition of anti-PD-1 further enhanced T cell function and promoted long-term survival. These findings highlight BRCA1's role in cancer vaccine sensitivity and support rational combination immunotherapies for BRCA1-mutated OC.

Keywords:  BRCA1 mutation; PARP inhibition; T cell exhaustion; cancer vaccine; immune checkpoint blockade; ovarian cancer

DOI:  https://doi.org/10.1016/j.isci.2026.116587
Int Immunopharmacol. 2026 Jul 22. pii: S1567-5769(26)01000-3. [Epub ahead of print]186 117154

A novel peptide-MHC-based T cell engager synergizes with tumor-targeted IL-12 for immunotherapy of solid tumors.

Shihui Wang, Qing Xu, Xueqian Peng, Xinman Li, Tianqing Zheng.

  Conventional CD3-targeting bispecific T cell engagers (BiTEs) have shown limited efficacy in solid tumors, largely due to the highly immunosuppressive tumor microenvironment (TME) and systemic T cell activation-associated toxicity. To address this challenge, we developed a peptide-MHC class I-based T cell engager platform that selectively redirects a specific subset of CD8+ T cells to tumor cells. Using the model ovalbumin (OVA) system, we engineered fusion proteins comprising an OVA peptide-H-2Kᵇ complex linked to an anti-HER2 nanobody (OVA-αHER2), enabling simultaneous engagement of OVA-specific T cells and HER2-expressing tumor cells and inducing potent tumor cell killing in vitro. To overcome the immunosuppressive TME, we further combined a HER2-targeted IL-12 fusion protein with OVA-αHER2, achieving synergistic anti-tumor responses in a mouse B16-HER2 solid tumor model. This treatment enhanced both systemic and intratumoral OVA-specific CD8+ T cell responses, accompanied by increased IFN-γ production in the TME. Together, these findings establish a modular immunotherapy strategy that integrates recruitment of a specific CD8+ T cell subset with localized cytokine-mediated immune reprogramming, providing a potential approach for HER2-positive solid tumors.

Keywords:  Antibody engineering; Cancer immunotherapy; Peptide MHC; Solid tumor; T cells; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.intimp.2026.117154
J Pathol Clin Res. 2026 Jul;12(4): e70108

Immune checkpoint profiling of B7-H proteins predicts survival and treatment response in metastatic clear cell renal cell carcinoma.

Maite Emaldi, Esther Rey-Iborra, Lorena Mosteiro, David Lecumberri, Ane Miren Iturregui, Jon Danel Solano-Iturri, María Armesto, Charles H Lawrie, Rafael Pulido, Javier C Angulo, José I López, Gorka Larrinaga, Caroline E Nunes-Xavier.

  The B7-H family of immune checkpoint proteins plays a central role in tumor immune regulation, yet their prognostic and predictive significance in metastatic clear cell renal cell carcinoma (ccRCC) remains incompletely defined. We analyzed a retrospective cohort of primary tumor specimens from 145 patients with synchronous or metachronous metastatic ccRCC to evaluate the expression of B7-H3, B7-H4, B7-H5, and B7-H7 and their association with tumor aggressiveness, treatment response, and long-term survival. Immunohistochemistry revealed marked intratumoral heterogeneity and distinct compartmentalized expression patterns, with B7-H3 detected in both tumor cells and stromal compartments, B7-H4 exclusively expressed in tumor cells, B7-H5 localized to tumor cells and tumor-infiltrating lymphocytes (TILs), and B7-H7 detected in both tumor cells and TILs. We did not detect any overlap in expression between B7-H proteins and PD-L1 positivity in TILs. High B7-H3 expression in tumor and stroma was significantly associated with higher histological grade, increased local invasion, lymph node involvement, and advanced stage. B7-H5 expression in TILs correlated with impaired Eastern Cooperative Oncology Group performance status. Elevated B7-H3 predicted unfavorable response to tyrosine kinase inhibitors, mechanistic target of rapamycin inhibitors, and immune checkpoint inhibitors, whereas B7-H5 negativity in tumor cells associated with more favorable treatment outcomes. B7-H4 and B7-H7 expression in tumor cells were associated with features of tumor aggressiveness and immune suppression, further highlighting the potential role of multiple B7-H family checkpoints in metastatic ccRCC. In multivariable Cox regression models, B7-H3 expression in tumor and stroma independently predicted shorter disease-free and overall survival. B7-H5 expression in TILs independently predicted reduced overall survival. These findings identify B7-H3 as a robust biomarker of tumor aggressiveness, therapeutic resistance, and adverse prognosis in metastatic ccRCC, while B7-H5 in TILs provides complementary prognostic information. Integrated profiling of B7-H immune checkpoints in primary tumors may refine clinical risk stratification and support the development of biomarker-guided immunotherapeutic strategies.

Keywords:  B7‐H3; B7‐H4; B7‐H5 (VISTA); B7‐H7; clear cell renal cell carcinoma (ccRCC); immune checkpoint proteins; prognostic biomarker; treatment response; tumor microenvironment

DOI:  https://doi.org/10.1002/2056-4538.70108
Brain Tumor Pathol. 2026 Jul 20.

Association between PLVAP downregulation and increased lymphocyte infiltration in newly diagnosed glioblastoma treated with bevacizumab.

Hiroaki Matsuzaki, Shukang Zhao, Yoshihiro Komohara, Cheng Pan, Rin Yamada, Daiki Yoshii, Yukio Fujiwara, Hiromu Yano, Ai Iwauchi, Nei Fukasawa, Masayuki Shimoda, Akitake Mukasa, Toshihide Tanaka.

  Glioblastoma (GBM) is a highly lethal brain tumor resistant to immunotherapy such as immune checkpoint inhibitors, partly because of an immunosuppressive tumor microenvironment and blood-brain barrier (BBB) dysfunction. Although bevacizumab can remodel the tumor vasculature, the relationship between BBB-related vascular changes and immune cell infiltration in GBM remains poorly understood. We analyzed human isocitrate dehydrogenase (IDH)-wildtype GBM tissues obtained after bevacizumab administration. Immunohistochemistry was performed for CD34 and plasmalemma vesicle-associated protein (PLVAP/PV-1), an endothelial marker associated with BBB disruption. Infiltrating T cells (CD3, CD8) and tumor-associated macrophages/microglia (TAMs; CD163) were also examined. PLVAP was broadly expressed in tumor vessels of untreated GBM and significantly reduced after bevacizumab administration, with marked downregulation in 3 of 10 treated cases. Among the 10 treated cases, significant increases in T-cell and cytotoxic T-lymphocyte infiltration were seen in PLVAP-low GBM compared with PLVAP-high GBM. TAM density did not differ significantly between groups but tended to be higher in the PLVAP-low group. These findings suggest that the bevacizumab-associated reduction of PLVAP expression is linked to increased T-cell infiltration in a subset of GBM cases. PLVAP may serve as an auxiliary histological marker for evaluating bevacizumab-related vascular/BBB remodeling in clinical specimens.

Keywords:  Blood brain barrier; Glioblastoma; PLVAP; PV-1; Tumor-associated macrophage/microglia; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1007/s10014-026-00546-2
Cell Rep Methods. 2026 Jul 22. pii: S2667-2375(26)00234-1. [Epub ahead of print] 101533

Efficient generation of human cDC1-like cells to detect and enhance tumor-reactive T cells via CD4+ T cell help.

Yizhi Wang, Xin Lei, Tom de Wit, Ellen Schrama, Marij J P Welters, Karel van Leeuwen, Sander de Kivit, Miriam de Boer, Jitske van den Bulk, Noel F C C de Miranda, Ton N Schumacher, Chong Sun, Jannie Borst, Yanling Xiao.

  Classical type 1 dendritic cells (cDC1s) are crucial to anti-tumor immunity by cross-presenting tumor antigens and priming cytotoxic CD8+ T lymphocytes (CTLs). Licensing via CD4+ T cell help endows cDC1s with enhanced cross-presentation and CTL-priming capacity, making them a promising tool to improve adoptive T cell therapies. However, the scarcity of primary human cDC1s limits their in-depth translational investigation and application. Here, we describe a method to efficiently generate DCs in vitro from CD34+c-KIT+ progenitors in non-mobilized peripheral blood. This DC population is enriched for cDC1-like cells that respond to CD4+ T cell help by upregulation of key molecules involved in antigen cross-presentation and T cell costimulation. Upon CD4+ T cell-mediated licensing, the progenitor-derived DC promotes tumor-specific CTL priming and facilitates detection of rare tumor antigen-specific CD8+ T cells in blood and tumor tissues. This DC culture platform incorporating CD4+ T cell help provides a scalable system for immunomonitoring and optimizing adoptive T cell therapies in cancer.

Keywords:  CP: cancer biology; CP: immunology; adoptive cell therapy; blood progenitor; cDC1-licensing; cDC1-like cell generation; tumor antigen-specific CTL

DOI:  https://doi.org/10.1016/j.crmeth.2026.101533
Hum Mutat. 2026 ;2026 2370955

Multiomics Analysis Reveals CTHRC1+ CAFs Drive Immunosuppressive Niches and Predict Immunotherapy Resistance in Gastric Cancer.

Yingxin Wu, Ling-Han Tang, Ping Li, Jianwei Xie, Chaohui Zheng, Changming Huang, Hua-Ping Ye, Yan-Jun Liu.

  Cancer-associated fibroblasts (CAFs) orchestrate immune-excluded tumor microenvironment (TME), but the CAF heterogeneity remains incompletely understood in gastric cancer (GC). In this study, we integrated multicohort single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and bulk transcriptomic data to construct a comprehensive atlas of the GC TME. Unsupervised clustering identified eight transcriptionally distinct CAF subpopulations, among which CTHRC1+ CAFs were selectively enriched in tumors and showed the strongest association with T cell exclusion. Pseudotemporal trajectory analysis, gene regulatory network inference, and cell-cell communication analysis revealed that basic helix-loop-helix family member e41 (BHLHE41) serves as a key transcription factor driving CTHRC1+ CAF differentiation, whereas spatial analyses demonstrated these fibroblasts contribute to fibrotic niches at the tumor-stroma interface through macrophage migration inhibitory factor (MIF)-mediated signaling. Finally, we developed and validated a CTHRC1+ cancer-associated fibroblast-related risk signature (CRS) that accurately predicts immunotherapy response across independent cohorts. These findings establish CTHRC1+ CAFs as a critical stromal determinant of immune exclusion in GC, suggesting that targeting the CTHRC1+ CAF-MIF axis or applying CRS-guided patient stratification may enhance immunotherapy efficacy.

Keywords:  cancer-associated fibroblasts; gastric cancer; immune exclusion; immunotherapy; multiomics

DOI:  https://doi.org/10.1155/humu/2370955
Cancer Res. 2026 Jul 23.

Parallel 4-1BB Signaling in Dual DLL3/CD56-Targeting CAR-T Cells Triggers Adaptive Proliferation and Functional Persistence to Eradicate Small Cell Lung Cancer.

Yan-Na Lei, Diyuan Qin, Yan He, Pei Shu, Benxia Zhang, Yue Chen, Ning Liu, Xia He, Yu-Gu Zhang, Meng-Yao Chang, Xiaoyu Li, Fu-Chun Guo, Liang-Liang Bai, Mingyang Feng, Fu-Jue Wang, Yu Gao, Bo Zhu, ZhongJun Li, Dan Li, Yong-Sheng Wang, Yuquan Wei.

Limited intratumoral persistence and insufficient proliferative capacity severely restrict the efficacy of chimeric antigen receptor (CAR)-T cell therapies in solid tumors. Here, we demonstrated that DLL3-targeting CAR-T cells co-expressing a CD56 chimeric switch receptor (CSR) and incorporating parallel 4-1BB costimulatory signaling (DBBζ.CBB) effectively address these limitations. In preclinical small cell lung cancer (SCLC) models, DBBζ.CBB exhibited sustained tumor infiltration, prolonged persistence, and superior antitumor activity. Mechanistically, parallel 4-1BB signaling dynamically programed CAR-T cell fate by promoting early expansion and memory maintenance, driving a highly proliferative effector state at the intermediate stage, and delaying terminal exhaustion at the later stage, thereby sustaining in vivo persistence and enabling durable antitumor responses. Building upon the intratumoral T-cell pool established by DBBζ.CBB, subsequent DLL3 trispecific T-cell engager (TriTCE) administration synergistically enhanced tumor eradication by further boosting CD8+ T cell infiltration and overall activation while mitigating exhaustion and terminal differentiation. Collectively, these findings establish a clinically translatable combinatorial framework to enhance the efficacy and durability of CAR-T therapy in solid tumors.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-5261
Cancer Cell Int. 2026 Jul 20.

CAR-T and TIL therapies in solid tumors: barriers, clinical lessons, and convergent solutions.

Duc-Hiep Bach, Van T Hoang, Thi Viet Pham, Huong, Dinh Duy Nguyen, Thanh Liem Nguyen.

The approval of lifileucel in 2024 marked an important milestone in oncology as the first cellular therapy authorized for a solid tumor. This milestone stands in sharp contrast to the success of CAR-T cells in hematologic malignancies, where six products have been licensed, and highlights the central challenge that solid tumors remain largely unconquered. At the mechanistic core lies a three-stage framework describing the major barriers encountered by therapeutic T cells in solid tumors, a series of escalating barriers that any therapeutic T cell must overcome to achieve durable tumor control: (1) Access: overcoming stromal and vascular barriers that restrict T-cell infiltration into tumors, (2) Recognition: identifying malignant cells in the setting of antigen heterogeneity and immune evasion, and (3) Persistence: maintaining T-cell function within the immunosuppressive tumor microenvironment. Historically, CAR-T and TIL therapies were viewed in competition, each occupying distinct niches. The field is increasingly adopting a convergent paradigm in which both platforms address a common challenge: overcoming the biological barriers that limit durable responses in solid tumors through complementary engineering and biological strategies. We review the biological obstacles, emerging convergence strategies, and translational frameworks including biomarker-guided patient selection that define this new area. Therapeutic selection may increasingly be guided by a tumor's dominant biological barriers rather than by platform classification alone.

DOI: https://doi.org/10.1186/s12935-026-04425-w
Front Immunol. 2026 ;17 1823199

BAG3+ CAF-T cell neighborhood predicts resistance to neoadjuvant chemoimmunotherapy in NSCLC.

Jing Sun, Zhengqi Cao, Yueping Jin, Anni Wang, Li Lu, Lixuan Chen, Wenhui Shi, Peiyi Xu, Yuxin Ouyang, Junjie Tang, Zhouwenli Meng, Ziming Li.

   Background: Despite significantly improving outcomes in non-small cell lung cancer (NSCLC), neoadjuvant chemoimmunotherapy (NCIT) fails to achieve a major pathological response (MPR) in over 40% of patients. Consequently, the early identification of non-responders prior to treatment initiation remains a critical unmet clinical need.
Methods: In this study, we performed single-cell RNA sequencing (scRNA-seq) on pre-treatment NSCLC tissue samples and integrated data from two public databases to identify signaling pathways associated with poor treatment response. Key findings were subsequently validated using multiplex immunofluorescence (mIF), and the predictive value of identified molecules was finally assessed in our cohort and GEO datasets.
Results: Among the 83 patients, 23/57 (40.35%) of these radiological responders failed to achieve MPR. Data analysis revealed activation of stress-related signaling pathways in cancer-associated fibroblasts (CAFs) and T cells from nMPR patients, with elevated expression of stress-related markers, including BAG3 and IFITM2. MIF confirmed that BAG3+IFITM2+ CAFs and BAG3+CD8+ T cells were spatially adjacent and significantly more abundant in nMPR patients. In our cohort and the two public databases, the BAG3+ CAF-T Cell Neighborhood was significantly more abundant in the nMPR group compared to the MPR group (p<0.05). In the MPR group, there was no significant difference in BAG3+ CAF-T Cell Neighborhood between the radiological PR and non-PR subgroups. The AUC values of BAG3+IFITM2+ CAFs, BAG3+CD8+ T cells, and the BAG3+ CAF-T Cell Neighborhood were 0.84 [95%CI: 0.746-0.931], 0.72 [95%CI: 0.603-0.835], and 0.87 [95%CI: 0.787-0.948], respectively. The OS and DFS of the BAG3+ CAF-T Cell Neighborhood high group are significantly decreased than that of the low group (p<0.05). The level of BAG3+ CAF-T Cell Neighborhood outperformed other two indicators in predicting non-response to NCIT. Consistent results were observed in GSE126044 and GSE135222.
Conclusion: The BAG3+ CAF-T Cell Neighborhood may serve as a biomarker for predicting non-response to NCIT in NSCLC, with significant potential to inform clinical decision-making.

Keywords:  BAG3+ CAF-T cell neighborhood; biomarker; cancer-associated fibroblasts (CAFs); neoadjuvant chemoimmunotherapy (NCIT); non-small cell lung cancer (NSCLC)

DOI:  https://doi.org/10.3389/fimmu.2026.1823199
iScience. 2026 Jul 17. 29(7): 116505

Computational identification of antigen-specific T cell groups through generative epitope modeling.

Minuk Ma, Wilson Tu, Carlos Vasquez-Rios, Jiarui Ding.

  Single-cell T cell receptor (TCR) sequencing enables high-resolution analysis of TCR diversity and clonal expansion. However, inferring antigen specificity for individual TCRs remains challenging and typically requires costly functional assays. We introduce EpitopeGen, a transformer-based model that generates candidate epitope sequences from TCR sequences, enabling population-level identification of T cell groups with shared predicted antigen specificity. EpitopeGen employs a semi-supervised strategy that searches over 70 billion candidate TCR-epitope pairs and incorporates high-confidence binding predictions as pseudo-labels under biologically inspired quality control. Generated epitopes exhibit high predicted binding probabilities, sequence diversity, realistic biochemical properties, and biophysical stability. In cancer datasets, EpitopeGen identifies clonally expanded tumor-infiltrating CD8+ T cells enriched for tumor-associated antigen recognition and cytotoxic signatures. In patients with COVID-19, it reveals distinct transcriptomic profiles of T cells targeting spike and non-structural proteins across disease severities. EpitopeGen provides a scalable framework for studying disease-associated T cell populations, complementing experimental antigen validation.

Keywords:  Biological sciences

DOI:  https://doi.org/10.1016/j.isci.2026.116505
J Transl Med. 2026 Jul 21.

TCM-derived immunometabolic modulators as systems adjuvants for CAR-T therapy in solid tumors: evidence hierarchy and translational roadmap.

Fei Wang, Feng Ji.

   BACKGROUND: Solid-tumor CAR-T therapy remains limited by antigen heterogeneity, stromal exclusion, abnormal vasculature, immunosuppressive myeloid and fibroblast niches, hypoxia, nutrient competition, mitochondrial stress and inflammatory toxicity. These barriers indicate that solid-tumor CAR-T therapy is not only a receptor-engineering problem but also a systems pharmacology problem requiring rational combinatorial modulation.
MAIN BODY: This review evaluates whether traditional Chinese medicine (TCM)-derived formulations, botanical compounds and microbiota-derived natural-product metabolites can be developed as mechanism-defined adjuvants for solid-tumor CAR-T therapy. We classify evidence by proximity to CAR-T systems, but also emphasize that evidence ranking must be interpreted within specific use cases. Current evidence remains limited and predominantly preclinical, yet it supports testable intervention concepts involving purified ex vivo metabolic conditioning, in vivo tumor conditioning, concurrent maintenance, toxicity modulation and delivery engineering. We further propose a translational framework linking product identity, exposure window, target annotation, immune-functional potency, CAR-T manufacturing compatibility, pharmacodynamic biomarkers, host-model suitability, lymphodepletion compatibility and safety assessment.
CONCLUSION: TCM-derived agents should not be developed as empirical supplements for CAR-T therapy. Translation should require defined product identity, target clarity, use-case-specific evidence, exposure window matched to product class, CAR construct, tumor context, manufacturing compatibility, immune-functional potency testing, suitable immune models, lymphodepletion drug-interaction assessment, safety assessment and biomarker-rich early-phase trials with explicit go/no-go criteria.

Keywords:  CAR-T; Solid tumors; T cell exhaustion; Traditional Chinese medicine; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12967-026-08672-3
Nature. 2026 Jul 22.

Tertiary lymphoid structures harbour stem-like tumour-specific T cells.

Alexander B Afeyan, Adi Nagler, Chloe R Tu, Gabriel Roberti De Oliveira, Berkay Simsek, Maxwell D Seager, Nourhan El Ahmar, Haley E Sax, Emma Lin, Amit Sud, Mehdi Borji, Cleo Forman, Sophia Liu, Patrick A Ott, Toni K Choueiri, Jennifer G Abelin, Richard Burack, Shuqiang Li, Kenneth J Livak, Svitlana Tyekucheva, Derin B Keskin, Fei Chen, Michael B Atkins, Jeremy M Simon, Sabina Signoretti, Giacomo Oliveira, David A Braun, Catherine J Wu.

Tertiary lymphoid structures (TLSs) are associated with improved responses to immune checkpoint blockade across solid tumours1,2, but how they impact the phenotypic properties of tumour-specific T cells remains unclear. Here we found, across 24 treatment-naive renal cell carcinoma (RCC) tumours, that TLS-containing tumours are more heavily infiltrated by exhausted CD8+ T cells and have a reduced terminal exhaustion transcriptional program compared with TLS- tumours. Specificity screening of 554 T cell clonotypes expanded within the microenvironment of 6 RCC tumours revealed 82 TCRs that were reactive against tumour cells and/or RCC antigens. A subset of tumour-specific T cell clonotypes (12%) was enriched within TLSs, and these expressed an increased program of stem-like progenitor exhaustion, associated with favourable anti-tumour immunity. However, in 60 independent RCC tumours, macrophages within tumour margins of TLS-containing tumours had an inferred immunosuppressive phenotype and were colocalized with exhausted putative tumour-reactive T cells in a subgroup that was further analysed, therefore supporting this mode of immune evasion as a counterbalance to T cell immune pressure. Our data reveal that TLSs are reservoirs of tumour-specific T cells with stem-like progenitor features that could be leveraged by T cell immunotherapies.

DOI: https://doi.org/10.1038/s41586-026-10808-w
Front Immunol. 2026 ;17 1854351

Circulating immune and biochemical markers predict tumor response to immunotherapy in advanced melanoma and lung cancer.

Silvia Sequero-Lopez, Diego Castillo-Barnes, Laura Gálvez-Carvajal, Natalia Palazón-Carrión, Francisco Jesús Martínez-Murcia, Luis de la Cruz-Merino, Eva Muñoz-Couselo, Mariano Provencio, Andrés Ortiz, Juan Manuel Górriz, Javier Ramírez, Antonio Rueda-Domínguez, Isabel Blancas.

   Introduction: Peripheral immune biomarkers provide a minimally invasive approach to monitor systemic responses to cancer immunotherapy, yet their predictive value in real-world longitudinal settings remains incompletely defined.
Methods: We conducted a prospective longitudinal study in patients with advanced melanoma and non-small cell lung cancer (NSCLC) receiving immune checkpoint inhibitors. Thirteen circulating immune, inflammatory, and nutritional biomarkers were analyzed across treatment cycles, and their association with radiological response over time was assessed using Bayesian ordinal mixed-effects models.
Results: Nine biomarkers showed significant longitudinal associations with clinical outcomes. CD4+ T cells emerged as the strongest predictor of favorable response, followed by CD3+ and CD45+ T cells, natural killer cells, albumin, and total protein, whereas elevated neutrophils, lactate dehydrogenase, and the neutrophil-to-lymphocyte ratio were associated with poor outcomes. No significant effects were observed for CD8+ T cells, B cells, total lymphocytes, or the CD4/CD8 ratio.
Discussion: These findings identify circulating CD4+ T cells as the most informative peripheral biomarker associated with longitudinal response to immune checkpoint inhibitors and support the clinical utility of peripheral immune profiling as a dynamic, minimally invasive strategy for monitoring treatment efficacy in routine oncology practice.

Keywords:  Bayesian mixed-effects models; CD4+ T cells; circulating biomarkers; immune checkpoint inhibitors; longitudinal analysis; lymphocyte subpopulations; peripheral immune profiling

DOI:  https://doi.org/10.3389/fimmu.2026.1854351
Neurooncol Adv. 2026 Jan-Dec;8(1):8(1): vdag176

Twenty-year persistence of WT1-specific cytotoxic T lymphocytes in peritumoral brain tissue by peptide vaccine therapy: Transcriptomic evidence for resident memory T-cell induction.

Jun Nakata, Natsuki Nakamura, Daisuke Motooka, Chisato Yokota, Yoshiaki Hayashi, Ryuichi Hirayama, Fumihiro Fujiki, Soyoko Morimoto, Toru Umehara, Hiroko Nakajima, Yusuke Oji, Akihiro Tsuboi, Yoshihiro Oka, Atsushi Kumanogoh, Noriyuki Kijima, Haruhiko Kishima, Haruo Sugiyama.

   Background: Sustained immune surveillance at tumor sites is considered essential for effective cancer immunotherapy; however, direct evidence of immune surveillance in humans is limited due to difficulty obtaining tumor and peritumoral tissues through invasive procedures.
Methods: Peritumoral brain tissue was obtained during reoperation from a patient with diffuse astrocytoma who had received continuous Wilms' tumor gene 1 (WT1) peptide vaccination for 20 years. WT1 tetramer-positive CD8+ T cells were analyzed by flow cytometry, followed by T-cell receptor repertoire analysis and single-cell RNA sequencing.
Results: A high level of T-cell infiltration was observed in peritumoral brain tissue, despite the immune-privileged nature of the central nervous system. Notably, 38.4% of CD8+ T cells were WT1-tetramer positive, exhibiting an oligoclonal pattern similar to that observed in peripheral blood. Single-cell RNA sequencing demonstrated that WT1-specific cytotoxic T lymphocytes (CTLs) were predominantly composed of resident memory T cells (Trm) and terminally differentiated effector memory T cells (TEMRA), along with a small fraction of cycling T cells. Interestingly, Trm-like subsets were also detected among WT1-specific CTLs in peripheral blood.
Conclusion: These findings provide in situ evidence of long-term persistence of WT1-specific CTLs in the human brain by continuous WT1 peptide vaccination. Such local immune surveillance may have contributed to the prevention of relapse in this patient. Single-cell RNA sequencing suggests that long-lived Trm may contribute to the persistence of immune surveillance through self-renewal and generation of cytotoxic TEMRA. This study offers insights into long-term anti-tumor immunity and may inform future optimization of cancer vaccine therapy.

Keywords:  WT1 peptide vaccine; glioma; oligoclonal expansion; resident memory T cells; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1093/noajnl/vdag176
Eur J Cancer. 2026 Jul 15. pii: S0959-8049(26)00729-X. [Epub ahead of print]245 116948

Response to letter Re: "Progression risk among responders to PD-1/PD-L1 blockade is primarily stratified by response depth".

Mette Syberg Jespersen, Rikke Andersen, Marco Donia.

DOI: https://doi.org/10.1016/j.ejca.2026.116948
Mol Cancer Ther. 2026 Jul 24.

New Therapeutic Cancer Vaccine with Lenalidomide Induces Potent T Cell Immunity and Inhibits HPV E6/E7-Expressing Tumor Growth in Mice.

Yohannes Gemechu, Sonia Mukherjee, Jeffrey A Gelfand, Timothy A Brauns, Ann E Sluder, Pierre R Leblanc, Yuki Agarwala, James Adeosun, Abigail Colley, Daiki Sugita, Jacob J Smith, George Steinfels, Paul Korner, Ishan Capila, Patrick M Reeves, Mark C Poznansky.

Current prophylactic human papillomavirus (HPV) vaccines prevent infection but have limited therapeutic benefit in established HPV-driven malignancies. To address this unmet need, we developed VTX-067, a modular self-assembling therapeutic cancer vaccine consisting of a recombinant Mycobacterium tuberculosis heat shock protein 70-avidin fusion (MAV) noncovalently bound to biotinylated HPV E6/E7 MHC class I- and II-restricted peptide concatemers. MAV is produced in CHO cells with minimal endotoxin. Assembled VTX-067 is designed to elicit both CD4⁺ and CD8⁺ T-cell responses against HPV-associated tumors. In multiple tumor models expressing HPV E6/E7, intradermal vaccination with VTX-067 induced potent and dose-dependent HPV E6/E7-specific CD8⁺ and CD4⁺ T-cell responses without evidence of local reactogenicity. Therapeutic vaccination significantly delayed subcutaneous tumor progression, extended survival, and provided durable protection against tumor rechallenge. VTX-067 treatment increased intratumoral CD8⁺ T-cell infiltration, elevated the CD8:Treg ratio, and upregulated a Th1/cytotoxic transcriptional program including Ifnγ, Tbx21, Stat1, and Gzmb. Depletion of CD8⁺ T cells eliminated vaccine efficacy, while adoptive transfer of VTX-067-primed CD8⁺ T cells conferred tumor protection in recipient mice. In a cervicovaginal orthotopic model, both intradermal and intramucosal administration generated systemic E6/E7-specific effector responses and sustained control of mucosal tumors. Notably, combining a suboptimal VTX-067 dose with the immunomodulatory agent lenalidomide further enhanced tumor control and survival, demonstrating a potential dose-sparing strategy. These findings establish VTX-067 as a safe, highly immunogenic therapeutic vaccine with CD8⁺ T-cell-dependent antitumor activity, and support its clinical development alone or in combination with immune-modulating agents for HPV-associated cancers.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-1488