bims-tuinly 2026-08-23 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2026–08–23
fourteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

T cell receptor repertoire dynamics and newly identified functional regulators of autologous tumor-infiltrating lymphocyte therapy in advanced solid tumors.
An Open Source Automated Tumor Infiltrating Lymphocytes Algorithm for Prognosis in Primary Small Bowel Adenocarcinoma Using Routine Hematoxylin and Eosin Stained Sections.
Genetic Engineering of Tumor-Infiltrating Lymphocytes (TIL) via a T-Editor Platform to Enhance Anti-Tumor Activity.
The Relationship of CD4+, CD8+, and FOXP3+ Tumor-Infiltrating Lymphocytes and Their Ratios With Clinicopathological Parameters and Tumor Budding in Esophageal Squamous Cell Carcinoma.
Tumor-infiltrating lymphocytes density and distribution in breast cancer: A two-year study on their clinicopathological correlation.
Immune-cytokine signature predicts survival in patients with advanced melanoma treated with oncolytic adenovirus TILT-123 and chemotherapy and IL-2-free adoptive TIL therapy.
Tumor-derived PTX3 drives an immunosuppressive myeloid landscape and inhibits CD8 T cell-mediated anti-tumor immunity via PI3K-dependent signaling.
Anti-4CB1: A Novel Selective HVEM-Blocking Antibody Enhancing T-Cell and Macrophage Immunity Against Solid Tumors.
Mechanism of neoantigen generation and advances in neoantigen-based immunotherapies in colorectal cancer.
Personalized Neoantigen Vaccines Synergize with Immune Checkpoint Therapy and CD8-Targeted Cytokines to Control B-Cell Lymphoma.
Tumor-reactive LAG3+CD8+ T cells diverge into terminally exhausted cells and long-lived memory T cells.
A deep learning-derived risk score model from digital pathology to forecast nivolumab outcomes in gastric carcinoma.
Scalable generation of hematopoietic stem cell-engineered off-the-shelf mono-specific cytotoxic T cells targeting solid tumors.
A sonogenetic antigen-presenting nanoplatform enables spatiotemporal control of calcium signalling in T cells for enhanced cancer immunotherapy.

J Transl Med. 2026 Aug 11. pii: 1068. [Epub ahead of print]24(1):

T cell receptor repertoire dynamics and newly identified functional regulators of autologous tumor-infiltrating lymphocyte therapy in advanced solid tumors.

Fenge Li, Jilong Yang, Gregory Lizee, Yongming Xue, Ruijing Wang, Chao Zhang, Xinbo Gao, Xiangqin Zhao, Mei Liu, Wenhan Lu, Yupeng Wang, Weihong Feng, Chunhua Ma, Ying Ma.

BACKGROUND: Tumor-infiltrating lymphocyte (TIL) therapy has demonstrated clinical potential in melanoma; however, its applicability across diverse solid tumors in Asian patients remains unclear. Identification of molecular targets to enhance the antitumor activity of TIL is urgently needed.
MATERIALS AND METHODS: In a phase I investigator-initiated trial, we evaluated the safety, feasibility, and preliminary efficacy of autologous TIL therapy in twelve patients with advanced melanoma, cervical, lung, or head and neck cancers. Twelve patients who had progressed after standard therapies were enrolled between August 2022 and December 2024. Patients received lymphodepletion with cyclophosphamide (30 mg/kg) for 2 days, followed by fludarabine (25 mg/m²) for 5 days, approximately 24 h before intravenous infusion of autologous TIL. High-dose interleukin-2 (IL-2) was administered for 6-12 days to support T-cell survival and expansion. After a 28-day safety observation period, tumor assessments were performed every 6 weeks for the first 6 months and thereafter every 12 weeks during long-term follow-up, according to RECIST 1.1 criteria. T cell receptor (TCR) sequencing was conducted to evaluate in vivo persistence of infused TIL. Differential gene expression analysis was performed using bulk RNA sequencing on TIL from responders and non-responders. Target gene knockout in TIL was achieved using CRISPR/Cas9 technology to assess enhancement of antitumor function.
RESULTS: The most common adverse events were fever, anemia, nausea, hypertension, and hyponatremia. The objective response rate (ORR) was 33.3% (4/12), including one complete response (CR) and three partial responses (PR), with a disease control rate (DCR) of 75% (9/12). Infused TIL persisted in peripheral blood and induced a reversal in the peripheral CD4 + T to CD8 + T cell ratio. TCR sequencing revealed dynamic clonal remodeling in responders. Transcriptomic profiling identified ASS1 and CEP20 as genes negatively associated with therapeutic efficacy. CRISPR/Cas9-mediated knockout of ASS1 or CEP20 enhanced TIL memory phenotypes, cytokine production, and tumor cytotoxicity both in vitro and in vivo.
CONCLUSIONS: This study demonstrates the efficacy of TIL therapy in diverse solid tumors among Asian patients, reveals dynamic TCR clonal remodeling in responders, and identifies ASS1 and CEP20 knockout as strategies to potentiate antitumor activity. These findings provide mechanistic insights that may guide improvement of TIL therapy for broader clinical application.
TRIAL REGISTRATION: NCT, NCT05366478. Registered 01 August 2022, http://www.
CLINICALTRIAL: gov/NCT05366478 .

DOI: https://doi.org/10.1186/s12967-026-08781-z
Cancer Med. 2026 Aug;15(8): e72024

An Open Source Automated Tumor Infiltrating Lymphocytes Algorithm for Prognosis in Primary Small Bowel Adenocarcinoma Using Routine Hematoxylin and Eosin Stained Sections.

Minying Deng, Xin Liu, Yuanlong Luo, Ayizimugu Abuduwaili, Qi Song, Rongkui Luo, Wen Huang, Lei Xu, Xiaolei Zhang, Lin Sun, Jieakesu Su, Chen Xu, Yingyong Hou.

   OBJECTIVE: While tumor-infiltrating lymphocytes (TILs) are prognostic in various cancers, their role in small bowel adenocarcinoma (SBA) is unexplored. This study evaluates the prognostic significance of digitally quantified TILs in SBA.
METHODS: Using digital pathology (QuPath) on hematoxylin and eosin (H&E)-stained slides from 62 SBA cases, we quantified tumor cells, TILs (lymphocytes & plasma cells), and stromal components. Derived variables (eTILs, etTILs, esTILs, eaTILs, sTILs, iTILs, easTILs, and tumor-stroma ratio [TSR]) were correlated with clinicopathological features and survival. To account for multiple comparisons across all statistical tests, false discovery rate (FDR) correction was applied.
RESULTS: Several TIL-related parameters showed suggestive associations with clinicopathological features (p < 0.05), though none remained significant after FDR correction. In univariate survival analysis, M stage and TNM stage were strongly associated with disease-free survival (DFS) and remained highly significant after FDR correction (both q < 0.001). Regarding TIL-related parameters, higher eTILs (p = 0.028) and iTILs (p = 0.032) showed suggestive associations with prolonged overall survival (OS) in univariate analysis, and higher iTILs also showed a suggestive association with DFS (p = 0.045); however, none of these associations remained significant after FDR correction. In multivariate analysis, M stage and TNM stage were confirmed as independent prognostic factors for DFS, while eTILs (p = 0.099) and tumor deposit (p = 0.055) showed trends toward independent prognostic significance without reaching statistical significance.
CONCLUSION: This study, for the first time, objectively quantifies TILs in SBA, a rare tumor, using digital pathology and explores the potential prognostic significance of TILs in SBA. TIL-related parameters demonstrate suggestive trends that warrant validation in larger, independent cohorts. These findings provide a foundation for future studies to clarify the role of TILs in SBA.

Keywords:  QuPath; TILs; biomarker; prognosis; small bowel adenocarcinoma

DOI:  https://doi.org/10.1002/cam4.72024
Cancer Sci. 2026 Aug 19.

Genetic Engineering of Tumor-Infiltrating Lymphocytes (TIL) via a T-Editor Platform to Enhance Anti-Tumor Activity.

Fenge Li, Xuejiao Ma, Yongming Xue, Jilong Yang, Ruijing Wang, Xiang Li, Chao Zhang, Wenhan Lu, Mei Liu, Yue Xu, Xinyi Wang, Shengnan Wu, Ning Kang, Chunhua Ma.

  Tumor-infiltrating lymphocytes (TIL) therapy has demonstrated clinical potential in malignancies. However, limited understanding of why only a subset of patients respond to TIL therapy, coupled with the lack of simple and efficient methods to genetically engineer fragile TIL, has hindered efforts to enhance TIL efficacy through genetic modification. A T-Editor platform enabling rapid and efficient CRISPR-mediated gene editing in TIL was developed and optimized. To minimize the risk of chromosomal translocations associated with Cas9-induced double-strand breaks (DSBs), single-guide RNAs (sgRNAs) were designed for cytosine base editing (CBE). The expansion capacity, phenotypic profile, cytokine production, and in vitro cytolytic activity of base-edited TIL were compared with those of Cas9-KO TIL. In vivo efficacy was assessed using patient-derived xenograft (PDX) mouse models. The T-Editor platform was optimized for TIL gene editing by refining stimulation conditions, electroporation parameters, and CRISPR/Cas9 reagent dosing. FAM84B emerged as the top candidate, with its knockout resulting in the most pronounced enhancement of TIL cytolytic activity. CBE-mediated C·G-to-T·A conversion in the FAM84B exon achieved high editing efficiency with minimal insertion-deletion (indel) events. Base-edited TIL exhibited comparable expansion, phenotype, cytokine production, and in vitro cytolytic activity relative to Cas9-KO TIL. Compared with non-engineered control TIL, FAM84B-edited TIL displayed an increased CD62L+ memory subset, enhanced effector function and cytolytic activity, and improved in vivo antitumor efficacy. In conclusion, the T-Editor platform enables rapid and efficient CRISPR-mediated gene editing for engineering TIL to enhance its therapeutic potency. FAM84B may represent a novel potential target for improving TIL-mediated antitumor activity.

Keywords:  CRISPR/Cas9; FAM84B; T‐editor platform; cytosine base editor; tumor‐infiltrating lymphocytes (TIL)

DOI:  https://doi.org/10.1111/cas.70502
Int J Surg Pathol. 2026 Aug 18. 10668969261467697

The Relationship of CD4+, CD8+, and FOXP3+ Tumor-Infiltrating Lymphocytes and Their Ratios With Clinicopathological Parameters and Tumor Budding in Esophageal Squamous Cell Carcinoma.

Burcin Ergul, Ebru Sener, Yener Aydin.

  Esophageal squamous cell carcinoma is the most common histological subtype of esophageal cancer, and novel therapeutic strategies, including immunotherapy, are increasingly needed to improve outcomes in advanced-stage disease. Identifying patients who may benefit from immunotherapy through individualized risk stratification and reliable prognostic biomarkers is therefore essential. This study aims to evaluate the association between tumor-infiltrating lymphocyte (TIL) subtypes (CD4+, CD8+, FOXP3+) and their ratios, with clinicopathological features, and tumor budding.The study included 75 patients diagnosed with esophageal squamous cell carcinoma who underwent esophagectomy without receiving preoperative neoadjuvant therapy. Sections best representing the tumor area and TILs were selected, and immunohistochemical staining for CD4, CD8, and FOXP3 was performed. Positive lymphocytes were counted in 10 high-power fields at the invasive front. TIL densities were categorized as low or high based on mean counts. Tumor budding was assessed and classified as low, intermediate, or high grade.According to our results, low CD4+ TIL levels were significantly associated with poor histological grade, deeper tumor invasion, advanced pathological stage, and low tumor budding. High FOXP3+ TIL expression was associated with invasion depth and lymph node metastasis, whereas superficial tumors showed no high FOXP3 expression. A low FOXP3+/CD4+ ratio was correlated with longer survival. CD8+ TIL density alone showed no significant prognostic impact.In conclusion, combined assessment of TIL subtypes and tumor budding may contribute to improved prognostic stratification and postoperative treatment planning in esophageal squamous cell carcinoma.

Keywords:  CD4+ T cells; CD8+ T cells; FOXP3+ T cells; esophageal squamous cell carcinoma; tumor budding; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1177/10668969261467697
J Cancer Res Ther. 2026 Apr 01. 22(3): 582-589

Tumor-infiltrating lymphocytes density and distribution in breast cancer: A two-year study on their clinicopathological correlation.

Yamuna Jayakumar, Latha Abraham, T S Subi, Teena Sleeba, Sanju Cyriac, Jose Paul, Vijay Harish Somasundaram, Susan John, Anand Ebin Thomas.

   INTRODUCTION: Tumor-infiltrating lymphocytes (TILs) are emerging as key biomarkers in invasive breast carcinoma (IBC), reflecting the host immune response and influencing prognosis. While TILs are well-studied globally, data from the Indian subcontinent remains scarce. This study assesses stromal TILs (sTILs) and intratumoral TILs (iTILs) in an Indian cohort, investigating their associations with pathological features, clinical stage, and molecular subtypes.
METHODS: A retrospective observational study of consecutive IBC patients at a single Indian cancer center was conducted over two years and included. Demographic, pathological, and immunohistochemical (IHC) data (estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 [HER2], Ki67 proliferation index) were collected. TILs were evaluated on Hematoxylin and eosin (H and E) slides using International TILs Working Group (ITILWG) guidelines: sTILs expressed as a percentage of stromal area and iTILs semi-quantitatively (0-300). Correlations and group comparisons were analyzed using Spearman's rank correlation, Kruskal-Wallis tests, and multivariable linear regression.
RESULTS: A total of 326 patients were included. The median sTIL percentage was 7% (interquartile range [IQR] 5-38), and the median iTIL score was 60 (IQR 20-130). Higher median sTIL and iTIL levels were observed in triple-negative and HER2-enriched tumors, high-grade cancers, and hormone receptor-negative disease. Median sTIL percentages increased with tumor grade (grade 1: 5% [IQR 5-5]; grade 3: 35% [IQR 9-60]). Similar patterns were observed for iTILs. After Holm adjustment, associations with nuclear pleomorphism, mitotic activity, tumor grade, molecular subtype, Ki-67 category, and hormone receptor status remained statistically significant. In multivariable analyses using log-transformed TILs, molecular subtype and tumor grade were independently associated with higher sTIL and iTIL levels, while stage IV disease was associated with lower TIL levels compared with stage II.
CONCLUSIONS: This study confirms a strong correlation between sTILs and iTILs, suggesting sTIL assessment alone may suffice for routine practice. Higher TIL levels were significantly linked to more aggressive pathological features, such as higher tumor grade and triple-negative/HER2-enriched subtypes. While TIL levels varied with clinical stage, no consistent monotonic relationship was observed. Future research should integrate other biomarkers predictive of immunotherapy response and establish clinically actionable TIL cut-off values.

Keywords:  Breast cancer in Indian cohort; clinical and pathological correlation; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.4103/jcrt.jcrt_1656_25
J Immunother Cancer. 2026 Aug 20. pii: e016003. [Epub ahead of print]14(8):

Immune-cytokine signature predicts survival in patients with advanced melanoma treated with oncolytic adenovirus TILT-123 and chemotherapy and IL-2-free adoptive TIL therapy.

Lyna Haybout, Tatiana V Kudling, James H Clubb, Tine Juul Monberg, Benedetta Albieri, Santeri Artturi Pakola, Elise Jirovec, Victor Arias, Dafne C A Quixabeira, Susanna Juteau, Eva Ellebæk, Marco Donia, Rikke Løvendahl Eefsen, Troels Holz Borch, Torben Lorentzen, Helle Hendel, Cecilie Dam Vestergaard, Amir Khammari, Claudia Kistler, Marie Christine Wulff Westergaard, Özcan Met, Suvi Sorsa, Otto Hemminki, Anna Kanerva, Victor Cervera-Carrascon, Brigitte Dréno, Inge Marie Svane, Akseli Hemminki.

   BACKGROUND: Metastatic melanoma resistant to immune checkpoint inhibitors remains difficult to treat, and while adoptive tumor-infiltrating lymphocyte (TIL) therapy has shown durable responses, its reliance on lymphodepleting chemotherapy and high-dose interleukin (IL)-2 causes toxicity that may limit patient eligibility. The dual-cytokine-armed oncolytic adenovirus igrelimogene litadenorepvec (TILT-123) was administered with TILs in the TUNINTIL trial (trial registration: NCT04217473) in patients with metastatic melanoma resistant to immune checkpoint inhibitors, without lymphodepleting chemotherapy or IL-2 post-conditioning. This study presents a correlative immunological analysis of the phase I TUNINTIL trial evaluating TILT-123 in combination with TIL therapy.
METHODS: The TUNINTIL trial was a first-in-human, open-label, dose-escalation, multicenter, multinational phase I trial. 17 patients with checkpoint-inhibitor-resistant metastatic melanoma received up to six intratumoral TILT-123 injections followed by TIL infusion, without lymphodepleting chemotherapy or IL-2 post-conditioning. Systemic immune profiling (serum proteomics, flow cytometry, interferon-γ ELISpot assay), intratumoral immune cell-cell profiling (multiplex immunofluorescence, H&E, adenovirus E1a immunohistochemistry), quantitative PCR, and neutralizing antibody responses were assessed at defined time points through the trial, with survival follow-up updated to March 2026. Response criteria were evaluated using Response Evaluation Criteria in Solid Tumors V.1.1 and positron emission tomography-based criteria. Statistical analyses included Kaplan-Meier survival with log-rank tests, Mann-Whitney U tests, Pearson correlation, and receiver operating characteristic/area under the curve analysis for biomarker cut-off determination.
RESULTS: Tumor biopsy analyses revealed an early innate immune activation marked by natural killer-cell expansion and cytotoxic gene upregulation, followed by increased intratumoral T-cell infiltration. This occurred without lymphodepleting chemotherapy or post-conditioning IL-2. Intratumoral viral DNA was detectable in a subset of patients. The enrichment of CD27+CD28+ memory-precursor CD8+ T cell was associated with favorable clinical outcomes. Elevated monocytic myeloid-derived suppressor cells and angiogenic/inflammatory cytokines following combination treatment were associated with disease progression, highlighting the role of immunosuppressive myeloid subsets as potential mediators of therapeutic resistance. Additionally, correlative analysis in pooled TILT-123 cohorts identified serum epidermal growth factor as a candidate biomarker for stratifying and monitoring patients.
CONCLUSIONS: These findings provide mechanistic insights into TILT-123 combined with TIL therapy and propose future directions for biomarker-guided clinical studies.
TRIAL REGISTRATION NUMBER: NCT04217473.

Keywords:  Adoptive cell therapy - ACT; Biomarker; Cytokine; Oncolytic virus; Tumor infiltrating lymphocyte - TIL

DOI:  https://doi.org/10.1136/jitc-2026-016003
Oncogene. 2026 Aug 19.

Tumor-derived PTX3 drives an immunosuppressive myeloid landscape and inhibits CD8 T cell-mediated anti-tumor immunity via PI3K-dependent signaling.

Mohamed Y Zaky, Monika Vashisht, Mohammad A I Al-Hatamleh, Karen Siddoway, Jennifer Yan, Anthony Bragoli, Jessy John, Huaibin Ge, Zhangguo Chen, Jing H Wang.

Cancer immunotherapy, particularly immune checkpoint inhibitors (ICIs), has emerged as a pillar of modern oncology. However, clinical response rates in head and neck squamous cell carcinoma (HNSCC) remain modest, underscoring the need to identify novel therapeutic targets. Here, we investigated the role of Pentraxin 3 (PTX3) in orchestrating an immunosuppressive tumor microenvironment (TME) in HNSCC. Analysis of the TCGA dataset revealed that elevated PTX3 expression correlates with poor prognosis in HNSCC patients. Moreover, PTX3 is markedly upregulated in aggressive, ICI-resistant TAb2 tumors harboring an activated PIK3CA allele and TP53 deficiency. Using a CRISPR/Cas9 approach to delete PTX3 in TAb2 cells (PTX3-KO), we found that PTX3-KO tumors grew significantly slower than wild-type tumors in vivo. This reduced tumor growth was partially dependent on CD8+ T cells and occurred independently of tumor-intrinsic effects on cell proliferation. Genetic deletion of PTX3 profoundly reprogrammed the TME, increasing CD8+ tumor-infiltrating lymphocytes (TILs) and shifting the myeloid landscape by reducing immunosuppressive M2-like tumor-associated macrophages (TAMs) while promoting pro-inflammatory M1-like TAMs. Mechanistically, PTX3 drives M2-TAM polarization by activating downstream PI3K-γ/δ-dependent signaling, with evidence implicating the CD44 receptor. Crucially, anti-CD44 treatment or pharmacological blockade of PI3K-γ or PI3K-δ phenocopied the effects of PTX3 loss, substantially reducing M2-like TAMs and elevating M1-like TAMs. Collectively, our findings establish the innate immune molecule PTX3 as a critical regulator of myeloid-driven immune suppression in HNSCC. While PTX3 deficiency alone did not sensitize these models to PD-L1 blockade, therapeutic targeting of the PTX3-CD44-PI3K axis represents a promising strategy for remodeling the immunosuppressive TME.

DOI: https://doi.org/10.1038/s41388-026-03936-0
Mol Cancer Ther. 2026 Aug 19.

Anti-4CB1: A Novel Selective HVEM-Blocking Antibody Enhancing T-Cell and Macrophage Immunity Against Solid Tumors.

Gilli Galore-Haskel, Efrat Merhavi-Shoham, Mika Shapiro, Roni Bareli, Naama Dror, Sivan Seliktar-Ofir, Katerina Shamalov, Dorit Landstein, Adva Levy-Barda, Goni Hout-Siloni, Jacob Schachter, Eran Sadot, Ram Eitan, Iris Barshack, Shay Golan, Yael Feferman, Effi Yeoshoua, Saeb Eyadat, Eyal Greenberg, Gal Markel.

Immune checkpoint inhibitors (ICIs) have improved cancer outcomes; however, many patients fail to respond, highlighting the need for novel targets. HVEM (Herpes Virus Entry Mediator) is an immune regulator with both inhibitory and stimulatory functions, making it a promising therapeutic candidate. We have developed Anti-4CB1, a fully human monoclonal antibody (mAb) that selectively blocks HVEM interactions with BTLA and CD160. Its activity was evaluated in-vitro using human tumor-infiltrating lymphocytes (TILs), peripheral blood mononuclear cells (PBMCs), and M1 macrophages, as well as in ex-vivo patient-derived tumor samples and in-vivo transgenic and humanized mouse models. HVEM expression was also assessed in serum and tumor tissues. Anti-4CB1 enhanced T-cell activation and cytotoxicity, evidenced by increased tumor cell killing, upregulation of activation markers (41BB, CD107a), and elevated IFNγ and TNFα secretion. It also promoted macrophage-mediated phagocytosis. In ex-vivo analyses of 49 patient-derived tumor samples, Anti-4CB1 increased cytotoxicity in 28.5% of cases, including samples unresponsive to anti-PD1. In-vivo, Anti-4CB1 demonstrated significant anti-tumor activity as monotherapy and showed enhanced efficacy in combination with anti-PD1. Additionally, higher tumor HVEM expression correlated with improved response to checkpoint blockade, while elevated soluble HVEM levels were associated with reduced responsiveness to Anti-HVEM. Anti-4CB1 enhances both adaptive and innate anti-tumor immunity and shows activity in anti-PD1 resistant settings. These findings support its potential as a novel therapeutic agent and suggest HVEM as a predictive biomarker for immunotherapy response.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-1420
Med Oncol. 2026 Aug 20. pii: 246. [Epub ahead of print]43(9):

Mechanism of neoantigen generation and advances in neoantigen-based immunotherapies in colorectal cancer.

Na Wang, Yimeng Xia, Ping Wang, Yijia He, Kun Zhao, Zhe Zhang.

  Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality worldwide. Conventional therapeutic modalities-such as surgery, chemotherapy, and radiotherapy-yield suboptimal outcomes in advanced or recurrent disease, while immune checkpoint inhibitors demonstrate durable clinical benefit almost exclusively in the microsatellite instability-high (MSI-H) subset, which constitutes only ~ 15% of CRC cases. This stark therapeutic gap underscores an unmet medical need for novel, mechanism-driven immunotherapies. Tumor neoantigens-immunogenic peptides arising from somatic mutations and exclusively presented on malignant cells-represent highly promising targets for precision immunotherapy owing to their strict tumor-restricted expression and negligible risk of on-target, off-tumor toxicity. This review outlines the molecular mechanisms driving neoantigen generation in CRC, including frameshift mutations, single-nucleotide variants, alternative RNA splicing, and circular RNA-derived epitopes. We further delineate the immunological cascade by which these neoantigens are processed, presented via MHC molecules, and recognized by antigen-specific CD8+ and CD4+ T cells to elicit potent antitumor immunity. Subsequently, we evaluate neoantigen-directed therapeutic platforms, encompassing personalized neoantigen vaccines (peptide-, RNA-, and dendritic cell-based formulations, as well as innovative combinatorial delivery systems) and adoptive T-cell therapies-including tumor-infiltrating lymphocyte (TIL), chimeric antigen receptor T cells (CAR-T) and T cell receptor-engineered T cells (TCR-T)-that are engineered to recognize neoantigen-derived epitopes. Although challenges-including low tumor mutational burden (TMB), adaptive immune evasion, and spatially heterogeneous neoantigen expression-continue to impede broad clinical efficacy, emerging solutions-such as engineered exosome-based delivery, pharmacologic induction of neoantigen presentation (e.g., via RECTAS), and rationally designed combination regimens (e.g., with 5-fluorouracil or bevacizumab)-are demonstrating encouraging preclinical activity. Looking forward, strategic targeting of clonal driver mutation-derived neoantigens and accelerated clinical development of next-generation neoantigen vaccine platforms hold significant potential to redefine the treatment paradigm for patients with CRC.

Keywords:  Colorectal cancer; Immunotherapy; Neoantigen

DOI:  https://doi.org/10.1007/s12032-026-03357-9
bioRxiv. 2026 Aug 06. pii: 2026.08.02.742304. [Epub ahead of print]

Personalized Neoantigen Vaccines Synergize with Immune Checkpoint Therapy and CD8-Targeted Cytokines to Control B-Cell Lymphoma.

Yuang Song, Ekaterina Aladyeva, Ruan F Vieira Medrano, Derek J Theisen, Cora D Arthur, J Michael White, Heather Brink Kohlmiller, Anthony Vomund, Kartik Singhal, My Hoang, Samuel Ameh, Kathleen C F Sheehan, Ronald Levy, Todd A Fehniger, Maxim N Artyomov, Malachi Griffith, Obi L Griffith, Yik Andy Yeung, Ivana Djuretic, Hussein Sultan, Robert D Schreiber.

Personalized neoantigen (neoAg) vaccines have shown clinical promise in solid tumors 1-8 , yet their efficacy and mechanism of action in hematopoietic malignancies remain poorly defined 9-11 . Herein, we establish an immunocompetent syngeneic A20 B-cell lymphoma platform to test the efficacy of neoAg vaccines used either as mono- or combinatorial therapies with other immunotherapies 12-17 . Whereas subcutaneous A20 tumors were refractory to single-agent αPD-1 or αCTLA4 therapy, they were eradicated in a T cell-dependent manner in 90% of syngeneic hosts treated with dual immune checkpoint therapy (dual ICT, i.e., αPD-1 + αCTLA4). By mapping antigen specificity of dual-ICT-elicited T cells, we identified and validated dominant endogenous A20 MHC-I and MHC-II neoantigens and designed therapeutic synthetic long peptide (SLP) vaccines containing these neoepitopes. This vaccine (A20 neoVAX) promoted robust neoAg-specific CD4□ and CD8□ T cell responses in naïve syngeneic BALB/c mice and induced tumor rejection in ∼70% of subcutaneous tumor-bearing mice. In addition, nearly all mice rejected their subcutaneous A20 tumors when A20 neoVAX was combined with αPD-1. To render the results of this study more physiologic, we developed a systemic A20 lymphoma model and found that dual ICT failed to control tumor progression and A20 neoVAX delayed tumor progression and prolonged animal survival but did not induce tumor rejection. In contrast, A20 neoVAX plus dual ICT achieved durable systemic tumor elimination. Mechanistically, the combination of A20 neoVAX plus dual ICT amplified priming of A20 neoAg-specific T cells, prevented T cell dysfunction, sustained the cytotoxic capacity of tumor-specific CD8 + T cells, and induced Th1-skewing of CD4 + T cells in tumor and peripheral compartments. To increase the clinical relevance of these findings and to minimize potential adverse events in tumor-bearing, therapeutically treated individuals, we substituted CD8-targeted cytokine muteins (CD8-IL2 or CD8-IL21) for αCTLA4. These agents represent genetically modified forms of IL-2 or IL-21 that selectively stimulate CD8 + T cells but have significantly reduced capacity to activate chronic inflammation and immunosuppressive functions of other immune cells. Whereas mice bearing systemic A20 lymphoma treated with either nothing, A20 neoVAX, or A20 neoVAX + CD8-IL2 failed to control tumor outgrowth, 66.7% of tumor-bearing mice treated with A20 neoVAX + CD8-IL2 + αPD-1 rejected their tumors. In similar experiments in which CD8-IL21 was substituted for CD8-IL2, tumor clearance was also observed in two-thirds of A20-bearing mice but now rejection occurred in the absence of αPD1. Together, these data define a framework for optimal personalized neoAg vaccination in B-lymphoma and demonstrate that neoAg vaccines can safely synergize with CD8 + T cell-selective immunotherapies to prevent T-cell dysfunction and generate durable systemic anti-tumor immunity.

DOI: https://doi.org/10.64898/2026.08.02.742304
J Exp Med. 2026 Sep 07. pii: e20241968. [Epub ahead of print]223(9):

Tumor-reactive LAG3+CD8+ T cells diverge into terminally exhausted cells and long-lived memory T cells.

Vaishali Aggarwal, Yangxi Sun, Chang Liu, Jian Cui, Sasikanth Manne, Yingtong Dou, Qiang Chen, Erin A Brunazzi, Kate M Vignali, Haiguang Wang, E John Wherry, Creg J Workman, Dario A A Vignali.

Chronic T cell stimulation in tumors and chronic viral infections leads to T cell exhaustion, a state of dysfunction. As LAG3 marks a prominent subset of exhausted T (TEX) cells in mid-to-late stage tumors, we generated a Lag3 lineage-tracing mouse model (Lag3iCreERT2Rosa26LSL-tdTomato) to fate map and characterize tumor-reactive LAG3+CD8+ TEX cells. In tumor-bearing mice, two distinct tumor-specific tdTomato+ CD8+ T cell subsets stratified by LAG3 surface expression (LAG3+tdT+ and LAG3-tdT+) exhibited contrasting anatomical distributions, functionality and transcriptional profiles, yet shared TCR clonotypes, suggesting a common origin. While LAG3+tdT+ CD8+ TEX cells were restricted to the tumor microenvironment and predominantly terminally exhausted, LAG3-tdT+ CD8+ TEX cells were progenitors that persisted in vivo and are required for anti-tumor immunity against a secondary tumor challenge. This study highlights TEX cell functional heterogeneity and plasticity and characterizes a unique fate-flexible LAG3-tdT+ progenitor TEX subset that drives an anti-tumor memory response, supporting antibody-based therapeutic targeting of LAG3+ TEX cells to unleash anti-tumor immunity and promote durability.

DOI: https://doi.org/10.1084/jem.20241968
Br J Cancer. 2026 Aug 21.

A deep learning-derived risk score model from digital pathology to forecast nivolumab outcomes in gastric carcinoma.

Yiyu Hong, Inwoo Hwang, Min-Ji Kim, Yuyeon Kim, Soomin Ahn, Jeeyun Lee, Kyoung-Mee Kim.

BACKGROUND: The PD-L1 combined positive score (CPS) is a biomarker predicting responses in gastric cancer (GC) immunotherapy.
OBJECTIVES: We aimed to develop a deep learning-based model to predict responses to nivolumab in GC using PD-L1 28-8 immunohistochemistry.
METHODS: A cell-detection network was trained on 1927 patches from 88 whole-slide images to generate a computational positive cell ratio (cPCR). The predictive performance of cPCR was evaluated in an independent cohort of 147 patients treated with nivolumab plus chemotherapy.
RESULTS: The overall objective response rate (ORR) was 49.66%. ORR was 56.12% in patients with PD-L1 CPS ≥ 5 and 36.73% in those with CPS < 5. Using cPCR, ORR was 56.03% for cPCR ≥5 and 25.81% for cPCR <5. The AUCs of CPS (0.586) and cPCR (0.601) did not differ significantly, but net reclassification analysis showed superior predictive performance for cPCR (p = 0.0269). Incorporating cPCR with tumour-stroma ratio through stepwise variable selection enabled construction of a risk-score model that improved prediction of immunotherapy benefit.
CONCLUSIONS: In conclusion, we developed a cPCR-based model and risk-score system that more accurately forecasts nivolumab response in GC, offering a promising tool for optimising immunotherapy selection.

DOI: https://doi.org/10.1038/s41416-026-03590-z
Cell Rep Med. 2026 Aug 19. pii: S2666-3791(26)00415-5. [Epub ahead of print] 102998

Scalable generation of hematopoietic stem cell-engineered off-the-shelf mono-specific cytotoxic T cells targeting solid tumors.

Yichen Zhu, Jiaji Yu, Yu Jeong Kim, Yanxin Tian, Zhe Li, Yuning Chen, Zibai Lyu, Enbo Zhu, Annabel S Zhao, Nathan Ma, Catherine Zhang, Adam Kramer, Matthew Wilson, Ryan Hon, Yu-Chen Wang, Siyu Lin, Xinyuan Shen, Zoe Hahn, Yuchong Zhang, Aijun Wang, Yan-Ruide Li, Lili Yang.

  Adoptive T cell therapy for solid tumors is limited by autologous manufacturing complexity and, in allogeneic settings, risks including graft-versus-host disease (GvHD), HLA restriction, and donor variability. We develop a scalable, feeder-free platform to differentiate gene-engineered hematopoietic stem and progenitor cells (HSPCs) into allogeneic, NY-ESO-1-specific cytotoxic T (AlloESO-T) cells. Product phenotype, function, tumor homing, and safety are assessed against solid tumor models and benchmarked to peripheral blood mononuclear cell (PBMC)-derived TCR-engineered T cells. AlloESO-T cells display a uniform cytotoxic phenotype, with dual tumor targeting through a transgenic TCR and natural killer receptors. Relative to PBMC-derived counterparts, AlloESO-T cells show superior cytotoxicity, selective solid-tumor homing, durable killing persistence, and resilience to immune evasion. They also maintain low GvHD and cytokine release syndrome risk, while retaining stable hypoimmunogenic features. These findings establish HSPC-derived AlloESO-T cells as an off-the-shelf, mono-specific cytotoxic T cell therapy with scalable manufacturing, enhanced efficacy, and improved safety, which support broad applicability of AlloESO-T cells across solid tumors.

Keywords:  CRS; ESO-T cell; GvHD; HSPC; NY-ESO-1-specific cytotoxic T cell; allogeneic cell therapy; cytokine release syndrome; graft-versus-host disease; hematopoietic stem and progenitor cell; mono-specific T cell therapy; off-the-shelf; solid tumor therapy; transgenic TCR; tumor homing

DOI:  https://doi.org/10.1016/j.xcrm.2026.102998
Biomaterials. 2026 Aug 15. pii: S0142-9612(26)00581-8. [Epub ahead of print]337 124557

A sonogenetic antigen-presenting nanoplatform enables spatiotemporal control of calcium signalling in T cells for enhanced cancer immunotherapy.

Qing Zhao, Wushuang Gong, Xuesha Xing, Fanshu Ma, Chenglong Wang, Yu Ding, Zheng Wang, Hang Zhou.

  Effective T-cell activation plays the critical role in cancer immunotherapy; however, strategies to precisely and sustainably stimulate antitumor T-cell responses while minimizing systemic toxicity remain limited. Here, we develop a sonogenetic artificial antigen-presenting cell (aAPC) platform for remote, spatiotemporally controlled Ca2+ influx in tumor-infiltrating T cells. The platform consists of poly (lactic-co-glycolic acid) nanoparticles loaded with the plasmid encoding the Mechanosensitive channel of large conductance (MSCL), coated with tumor-pulsed dendritic cell membranes to provide costimulatory signals, and conjugated with PD-1-targeting aptamers for T-cell-specific delivery. The nanoplatform exhibited high gene transfection efficiency within T cells and realize the expression of US (US)-responsive MSCL on the surface of T cells. Upon US irradiation, the engineered MSCL open, triggering controlled Ca2+ influx and activating downstream NFAT signalling. Therefore, sonogenetic aAPC results in the efficient and specific synergistic activation of T cells, improves the killing effects of T cells and ameliorated the dysfunction of exhausted T cells. In B16-F10 melanoma-bearing mice, sonogenetic aAPC promotes tumor infiltration and proliferation of CD8+ T cells, reduces immunosuppressive cells, and significantly suppresses tumor growth without eliciting adverse systemic immune-related events. This work demonstrates a safe and effective strategy for remotely potentiating T-cell-mediated antitumor immunity through precise sonogenetic control of calcium signalling.

Keywords:  Artificial antigen-presenting cells (aAPCs); Calcium signalling; Cancer immunotherapy; Sonogenetics; T cell exhaustion

DOI:  https://doi.org/10.1016/j.biomaterials.2026.124557