bims-tuinly 2026-01-25 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2026–01–25
23 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Tumor Infiltrating Lymphocytes in Cutaneous Squamous Cell Carcinoma-A Systematic Review.
Prognostic significance of programmed death-ligand 1 (PD-L1) and tumor-infiltrating lymphocytes (TILs) in glottic laryngeal cancer.
Reconstituting the head and neck tumor microenvironment with air-liquid interface organoids.
Safety and feasibility of blood-derived multiple antigen-specific endogenously derived T cells (MASE-T) for metastatic melanoma.
Supervised machine learning to quantitatively assess the prognostic value of tumor-infiltrating lymphocytes in gastric cancer.
Contrasting Prognostic Roles of Stromal Periostin Expression and Immune Cells Infiltration in Colorectal Carcinoma.
IL-7: a potential next-generation adjuvant for immune cell therapies.
GLUT1 expression, lymphocyte distribution and CD3+ T-cell metabolic subsets as predictive markers of response to immunotherapy in advanced melanoma.
Functionally heterogeneous intratumoral CD4+CD8+ double-positive T cells can give rise to single-positive T cells.
Dextran-based T-cell expansion nanoparticles for manufacturing CAR T cells with augmented efficacy.
Cell cycle arrest enhances CD8+ T cell effector function by potentiating glucose metabolism and IL-2 signaling.
Unveiling the myxofibrosarcoma tumor microenvironment: implications for immunotherapy.
Bispecific T cell engagers control solid tumors through clonal replacement and IL2-driven effector differentiation of CD8 T cells.
Targeting PDPN enhances antitumor T-cell activity by disrupting β-catenin-mediated PD-L1 expression in melanoma.
Phase I study of autologous T cells bearing fully human chimeric antigen receptors targeting mesothelin in mesothelin-expressing cancers.
UniTope & TraCR: A Universal Tool to Tag, Enrich, and Track TCR-T Cells and Therapeutic Proteins.
VHH-based CAR-T cells targeting Claudin 18.2 show high efficacy in pancreatic cancer models.
Improved Antitumor Activity of Interleukin-12-Secreting Chimeric Antigen Receptor T Cells Targeting CD176 across Different Carcinomas.
Tracking temporal shifts of peripheral blood NLR, PLR, and ALB: a prognostic tool for PD-1 inhibitor efficacy in advanced malignant melanoma.
Intratumoral Lactobacillus johnsonii Enhances Sensitivity to PD-1 Blockade by Inducing CD8+ T Cell Expansion in Hepatocellular Carcinoma.
Targeting thymidylate synthase enhances CD8 + T-cell infiltration and inhibits tumor growth in cervical cancer.
Unraveling CD8 lineage decisions reveals that functionally distinct CD8+ T cells are selected by different MHC-I thymic peptides.
Engineered CAR-NKT Extracellular Vesicles Suppress Tumor Progression and Enhance Antitumor Immunity.

Dermatopathology (Basel). 2026 Jan 13. pii: 6. [Epub ahead of print]13(1):

Tumor Infiltrating Lymphocytes in Cutaneous Squamous Cell Carcinoma-A Systematic Review.

Li Yang Loo, Shi Huan Tay, Choon Chiat Oh.

  Cutaneous squamous cell carcinoma (cSCC) is an immunogenic malignancy with variable immune infiltration and inconsistent responses to checkpoint blockade. Tumor-infiltrating lymphocytes (TILs) influence tumor progression and therapeutic outcome, yet their phenotypic and functional diversity across disease contexts remains incompletely understood. This review systematically characterizes the TIL landscape in human cSCC. Following PRISMA 2020 guidelines, PubMed and Embase were searched up to May 2025 and restricted to studies evaluating tumor-infiltrating lymphocytes in human cSCC, using the modified Newcatle-Ottawa score to assess risk of bias. Data were synthesized qualitatively given methodological heterogeneity. 48 studies met inclusion criteria. cSCCs exhibited dense CD3+ infiltrates composed of cytotoxic (CD8+GzmB+, Ki-67+, CD69+) and regulatory (FOXP3+, CCR4+) subsets. Higher CD8+ activity correlated with smaller tumors and longer disease-free survival, whereas FOXP3+ enrichment and TGF-β2 signaling promoted immune evasion. Immunosuppressed patients demonstrated diminished CD8+ density and clonality. Immune modulation with PD-1/PD-L1 blockade, imiquimod, HPV vaccination, or OX40 stimulation enhanced effector function. The cSCC immune microenvironment reflects a balance between cytotoxic and suppressive factors. Harmonizing multimodal immune profiling and integrating spatial context with systemic immune status may advance both prognostic stratification and therapeutic design.

Keywords:  immunology; immunosuppression; squamous cell carcinoma; tumor microenvironment; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3390/dermatopathology13010006
Indian J Pathol Microbiol. 2026 Jan 19.

Prognostic significance of programmed death-ligand 1 (PD-L1) and tumor-infiltrating lymphocytes (TILs) in glottic laryngeal cancer.

Kadic Muhedin, Zvrko Elvir, Vuckovic Ljiljana, Catic Sabina, Pot Danilo.

   AIM: The study aims to investigate the prognostic significance of programmed death-ligand 1 (PD-L1) and tumor-infiltrating lymphocytes (TILs) expression in glottic laryngeal carcinoma (LC) and assess the correlation of their expression.
MATERIALS AND METHODS: For this study, 40 patients who underwent complete resection of the glottic laryngeal tumor as primary treatment were selected. PD-L1 and TIL expression levels were determined by immunohistochemistry.
RESULTS: Disease-free survival (DFS) was statistically significantly longer in patients with the combined positive score (CPS). CPS ≥1 than those with CPS <1. The concentration of TILs in tumor specimens was not significantly related to gender, age, T status, N status, tumor, node, metastasis (TNM) stage, pathological grade, or locoregional recurrence. Multivariate Cox regression analysis showed that low CPS and positive nodal status are statistically significant and independent predictors of malignancy recurrence.
CONCLUSIONS: The findings of our study suggest that PD-L1 could be a valuable indicator for predicting recurrence and reduced survival following definitive therapy. Consequently, further comprehensive studies involving larger groups of patients are imperative to ascertain the predictive significance of PD-L1 and TIL as biomarkers in LC.

Keywords:  Laryngeal cancer; larynx; programmed death-ligand 1; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.4103/ijpm.ijpm_622_24
Front Oncol. 2025 ;15 1736505

Reconstituting the head and neck tumor microenvironment with air-liquid interface organoids.

Luxi Zheng, Wei Tang, Shuqi Guo, Lin Chen, Shoupeng Wang, Feng Liu, Jian Meng.

   Introduction: A patient-derived head and neck cancer organoid (HNCO) model that can reconstruct the tumor-immune microenvironment (TME) was established using air-liquid interface (ALI) culture technology. The Tumor-Infiltrating Lymphocytes (TILs) and cancer-associated fibroblasts (CAFs) could be maintained in this model for a certain period of time. This model was confirmed to simulate PD-1/PD-L1 checkpoint blockade, providing a reliable in vitro model for the verification and clinical prediction of the therapeutic effects of relevant immunotherapy drugs for head and neck cancer (HNC).
Methods: Fresh tumor tissue samples were obtained to establish an ALI head and neck cancer organoid (ALI-HNCO) model. The oncological characteristics of the organoids and their homology with parental tumors were verified using histomorphological analysis. T lymphocytes and fibroblasts in the organoids were detected using immunofluorescence staining. After treating with pembrolizumab (a PD-1 inhibitor), the secreted levels of the cytokine interferon-γ (IFN-γ) were measured using an enzyme-linked immunosorbent assay (ELISA), and changes in the ratio of CD8+/CD4+ distributed in the immune microenvironment of the organoid, as well as the expression of CD69+ immune cell subsets, were analyzed using flow cytometry. The FVS staining assay was used to verify the killing of tumor cells by cytotoxic T cells.
Results: The comparison of immunofluorescence in organoids and parental tumor tissues showed that CD3+ lymphocytes and SMA+ cells were also present in the active organoid tissues. Approximately 17.86% (5/28) of the ALI-HNCO model could amplify specific reactive CD8+ T lymphocytes, generating tumor specificity and cytotoxicity.
Discussion: An in vitro HNC immune microenvironment model was successfully constructed using the ALI method. This model maintained the proportions and structures of the components of the original tumor, such as tumor-infiltrating lymphocytes and cancer-associated fibroblasts, for a period of time in vitro, providing an experimental platform for exploring the complex crosstalk between HNC cells and multiple cell colonies. This study preliminarily validated the feasibility of using ALI organoid models to evaluate the efficacy of immunotherapy drugs in treating HNC, providing a reliable and stable preclinical model, and new ideas for drug screening platforms for personalized precision medicine in HNC.

Keywords:  air-liquid interface culture method; head and neck cancer; immune checkpoint inhibitors; immune microenvironment; organoids

DOI:  https://doi.org/10.3389/fonc.2025.1736505
Immunooncol Technol. 2026 Mar;29 101581

Safety and feasibility of blood-derived multiple antigen-specific endogenously derived T cells (MASE-T) for metastatic melanoma.

T J Monberg, S A Tvingsholm, M Svensson-Frej, C Vestergaard, M Ormhøj, J W Kjeldsen, T H Borch, R B Holmstroem, N Jayashankar, J S Granhøj, A R Cordt, S K Larsen, Ö Met, S R Hadrup, I M Svane.

   Background: Tumor-infiltrating lymphocyte (TIL) therapy is effective in metastatic melanoma (MM), but the need for resectable tumor tissue limits its accessibility. Antigen-presenting scaffolds (Ag-scaffolds) constitute a technology developed for the specific expansion of tumor-associated antigen (TAA)-specific T cells directly from peripheral blood. Ag-scaffolds are built on a dextran backbone with coattached interleukin 2 (IL-2), interleukin 21 (IL-21), and major histocompatibility complex class I molecules loaded with the top 30 most frequently expressed TAAs in MM patients. The resulting multiple antigen-specific endogenously derived T-cell (MASE-T) infusion product is enriched for CD8+ TAA-specific T cells. We hypothesize that treatment with MASE-T therapy is safe and feasible in patients with immune checkpoint inhibitor (ICI)-resistant MM.
Patients and methods: In this phase I, first-in-human, clinical trial (NCT04904185), six patients with ICI-resistant MM received MASE-T therapy preceded by 3 days of lymphodepleting chemotherapy with cyclophosphamide and fludarabine phosphate. The primary endpoint was the safety and feasibility of the treatment.
Results: MASE-T cells were successfully expanded in 88% (7/8) of the included patients, and most MASE-T products were enriched for T-cell populations targeting multiple TAAs. Administration of MASE-T therapy was safe with no MASE-T-related toxicities. Clinical efficacy was limited, with 3 out of 6 (50%) patients having stable disease 6 weeks after treatment.
Conclusions: This trial demonstrates that Ag-scaffold-driven expansion of TAA-specific T cells from the peripheral blood of patients with MM is feasible, and the resulting MASE-T infusion product can be safely administered. However, further development is required to unleash the full potential of this technology.

Keywords:  T-cell therapy; artificial antigen-presenting cells (aAPCs); metastatic melanoma

DOI:  https://doi.org/10.1016/j.iotech.2025.101581
BMC Cancer. 2026 Jan 19.

Supervised machine learning to quantitatively assess the prognostic value of tumor-infiltrating lymphocytes in gastric cancer.

Yinghao Luo, Yuanyuan Chen, Qian Xu, Honglei Chen, Jingping Yuan, Chunwei Peng, Linwei Wang.



Keywords:  Gastric cancer; Nomogram; Prognosis; QuPath; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1186/s12885-025-15421-0
Asian Pac J Cancer Prev. 2026 Jan 22. pii: 92037. [Epub ahead of print]27(1): 389-398

Contrasting Prognostic Roles of Stromal Periostin Expression and Immune Cells Infiltration in Colorectal Carcinoma.

Ghada Farghaly Abd-Elhamid, Moemen Mostafa Ahmed Hafez, Hanan Ahmed Mohammed Eltayeb, Noha Abd El Rahim Aboulhagag.

   BACKGROUND AND OBJECTIVES: Colorectal carcinoma (CRC) is one of the most common causes of cancer-related deaths worldwide. The prognosis of CRC patients is variable even within the same cancer stage. The tumor microenvironment (TME) plays a crucial role in CRC, yet its prognostic value remains incompletely understood. We hypothesize that different components of TME can affect patient outcomes in multiple ways. In this study, we assessed the prognostic implications of the desmoplastic reaction (DR) and immune cell infiltration within the TME of CRC through morphological and immunohistochemical (IHC) evaluation.
METHODS: A retrospective cohort of 65 CRC patients was examined. The patterns of DR and the density of tumor infiltrating lymphocytes (TILs) were evaluated in Hematoxylin and Eosin (H&E)-stained sections. IHC was performed for periostin (POSTN), CD8, CD4, and CD68. Associations with clinicopathological parameters and overall survival (OS), both in the entire study group and in the subgroup treated with adjuvant-therapy were investigated. The relation between different components of TME was also assessed.
RESULTS: High stromal POSTN expression correlated significantly with poor prognosis and reduced OS (p=0.005). High density of TILs in H&E-stained slides, CD8⁺, CD4⁺, and combined (CD8+CD4) T-lymphocytes was associated with improved OS (p=0.03, 0.02, p=0.03, and <0.001, respectively), while a high density of CD68+ macrophages was linked to poor prognosis (p=0.006). The combined (CD8+CD4) T-lymphocytes score emerged as an independent prognostic factor for OS (HR=0.1, p<0.001), outperforming the other studied parameters.
CONCLUSION: Stromal POSTN expression and immune cell infiltration, particularly combined (CD8+CD4), offer significant prognostic insights in CRC and may guide therapeutic decisions.

Keywords:  Colorectal carcinoma; Prognosis; Tumor Microenvironment; immune cells; periostin

DOI:  https://doi.org/10.31557/APJCP.2026.27.1.389
Front Immunol. 2025 ;16 1736931

IL-7: a potential next-generation adjuvant for immune cell therapies.

Richard S Hotchkiss, John F DiPersio, Cassian Yee, Russell K Pachynski, Marcel R M Van Den Brink.

  Cell-based immune therapies ranging from CAR-T cells to tumor infiltrating lymphocytes (TILs) and endogenous T-cell products, have produced unprecedented clinical responses in hematologic malignancies and are currently under active investigation for solid tumors. Nevertheless, several key challenges continue to limit the durability and breadth of clinical benefit. IL-7 is a pleiotropic cytokine that increases both the number and function of lymphocytes. Although not yet clinically approved, IL-7 has been used in over 620 adult and pediatric patients for a variety of reasons including, for example, to hasten bone marrow recovery after allogenic stem cell transplantation, to reverse lymphopenia due to HIV and idiopathic etiologies, to treat patients with various malignancies, and to boost vaccine responses. IL-7 is generally well-tolerated and effective in producing a durable increase in the number and function of CD4 and CD8 T cells. Recently, IL-7 has been used clinically in multiple myeloma patients receiving CAR-T cell therapy, in patients with urothelial cancer who are receiving checkpoint inhibitors, in patients undergoing endogenous lymphocyte cell therapy, and in critically-ill lymphopenic patients with COVID-19. The authors, all of whom have used IL-7 clinically, discuss how IL-7 effectively addresses all the major problems currently limiting adoptive cell therapies. Peering into the future, we believe that IL-7 will be a major advance as an adjuvant treatment in many cell therapies and hope that this commentary will expedite IL-7's testing in multiple clinical settings.

Keywords:  IL-7; TIL (tumor infiltrating lymphocytes); cancer therapy; car-t; chimeric antigen receptor T-cell immunotherapy; immunotherapy

DOI:  https://doi.org/10.3389/fimmu.2025.1736931
J Exp Clin Cancer Res. 2026 Jan 20.

GLUT1 expression, lymphocyte distribution and CD3+ T-cell metabolic subsets as predictive markers of response to immunotherapy in advanced melanoma.

Elizabeth C Paver, Tuba N Gide, Zarwa Yaseen, Paola Cornejo-Paramo, Peter Ferguson, Nigel G Maher, Alexander M Menzies, Matteo S Carlino, Ines Pires da Silva, Jeff Holst, Georgina V Long, Richard A Scolyer, James S Wilmott.



Keywords:  GLUT1; GLUT3; Immunotherapy; Melanoma; Metabolic tumor microenvironment; Multiplex immunofluorescence; Spatial distribution; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1186/s13046-025-03637-8
Proc Natl Acad Sci U S A. 2026 Jan 27. 123(4): e2506168123

Functionally heterogeneous intratumoral CD4+CD8+ double-positive T cells can give rise to single-positive T cells.

Tony Li, Arielle Ilano, Marcel Arias-Badia, Diamond Luong, Hewitt Chang, Serena S Kwek, Kathryn Allaire, Arun Chumber, Mason Sakamoto, Matthew Clark, Averey Lea, Mark Bridge, Brandon Chen, Eric Liu, Sima Porten, Maxwell V Meng, Lauren I R Erlich, David Y Oh, Lawrence Fong.

  Conventional single-positive (SP) CD4+ and CD8+ T cells recognize tumor antigens and help mediate clinical responses with cancer immunotherapy. Double-positive CD4+CD8+ (DP) T cells have also been described in human cancers, but their role in the tumor microenvironment remains unclear. By generating a multiomic single cell atlas of DP and SP T cells, we find that DP T cells possess phenotypic heterogeneity similar to SP T cells that includes multiple clonally expanded populations of cytotoxic DP T cells in human renal cell carcinoma (RCC). These intratumoral DP T cells can mediate both MHC class I- and class II-dependent killing of autologous tumor cells. In addition, transcriptional profiling of DP TCR-bearing T cells revealed a gene signature enriched for clinical responders to PD-1 blockade in advanced RCC. We confirm prior observations of SP T cells transitioning into DP T cells and more notably, demonstrate that intratumoral T cells are capable of bidirectional differentiation in which DP T cells serve as precursors to SP T cell sin vivo. In the latter scenario, intratumoral DP T cells are shown to express Rag2, suggesting that the tumor may act as an extrathymic site of T cell development. These findings reveal the multiple roles that DP T cells can possess in antitumor immunity.

Keywords:  T cells; immunotherapy; tumor immunity

DOI:  https://doi.org/10.1073/pnas.2506168123
Nat Commun. 2026 Jan 20.

Dextran-based T-cell expansion nanoparticles for manufacturing CAR T cells with augmented efficacy.

Tao Zheng, Keerthana Ramanathan, Maria Ormhøj, Mikkel Rasmus Hansen, Hólmfridur Rósa Halldórsdóttir, Hanxi Li, Kamilla Kjærgaard Munk, Carlos Rodriguez-Pardo, Rasmus Ulslev Wegener Friis, Islam Seder, Peter M H Heegaard, Klaus Qvortrup, Hinrich Abken, Yi Sun, Sine Reker Hadrup.

Adoptive T cell therapy using chimeric antigen receptor (CAR) engineered T cells is currently being explored in multiple cancer types beyond leukemia/lymphoma. A key step in CAR-T cell manufacturing is the activation and expansion of T cells, which facilitates viral transduction, however, may hamper T cell fitness and reduce in vivo persistence. "T-Expand" is developed for T cell activation and expansion, comprising dextran-based nanoparticles conjugated with anti-CD3 and anti-CD28 antibodies. The nanoparticles trigger robust polyclonal expansion of human T cells with efficiency in the range of commercial microbeads (Dynabeads™). Engineered in the presence of T-Expand, CD19 CAR T cells display enhanced proliferative capacity, cytotoxicity and persistence in vitro, and furthermore, exhibit potent anti-lymphoma activity in mouse models, resulting in complete tumor clearance at one fourth of the CAR T cell dose. Importantly, T-Expand is biocompatible with no observed toxicity, circumventing removal steps after T cell expansion compared to DynabeadsTM. As a biocompatible T cell expansion platform, T-Expand simplifies the manufacturing process while enhancing T cell persistence and functionality, and thereby holds promise for increasing clinical efficacy of CAR T cell therapy.

DOI: https://doi.org/10.1038/s41467-025-67868-1
Nat Immunol. 2026 Jan 19.

Cell cycle arrest enhances CD8+ T cell effector function by potentiating glucose metabolism and IL-2 signaling.

Floortje J van Haften, Tetje C van der Sluis, Hanna S Hepp, Nils Mülling, Reza Nadafi, Bharath Sampadi, Suzanne van Duikeren, J Shirin Mostert, Rosemarijn van der Sterre, Peter A van Veelen, Graham A Heieis, Dominique M B Veerkamp, Thomas H Wesselink, Ward Vleeshouwers, Macha Beijnes, Iris N Pardieck, Eralin L F van Horssen, Anne F de Groot, Manon van der Ploeg, Judith R Kroep, Noel F C C de Miranda, Sabina Y van der Zanden, Jacques Neefjes, Hailiang Mei, Alfred C O Vertegaal, Bart Everts, Sjoerd H van der Burg, Ramon Arens.

Cell cycle-inhibiting chemotherapeutics are widely used in cancer treatment. Although the primary aim is to block tumor cell proliferation, their clinical efficacy also involves specific effector CD8+ T cells that undergo synchronized proliferation and differentiation. How CD8+ T cells are programmed when these processes are uncoupled, as occurs during cell cycle inhibition, is unclear. Here, we show that activated CD8+ T cells arrested in their cell cycle can still undergo effector differentiation. Cell cycle-arrested CD8+ T cells become metabolically reprogrammed into a highly energized state, enabling rapid and enhanced proliferation upon release from arrest. This metabolic imprinting is driven by increased nutrient uptake, storage and processing, leading to enhanced glycolysis in cell cycle-arrested cells. The nutrient sensible mTORC1 pathway, however, was not crucial. Instead, elevated interleukin-2 production during arrest activates STAT5 signaling, which supports expansion of the energized CD8+ T cells following arrest. Transient arrest in vivo enables superior CD8+ T cell-mediated tumor control across models of immune checkpoint blockade, adoptive cell transfer and therapeutic vaccination. Thus, transient uncoupling of CD8+ T cell differentiation from cell cycle progression programs a favorable metabolic state that supports the efficacy of effector T cell-mediated immunotherapies.

DOI: https://doi.org/10.1038/s41590-025-02407-0
Front Immunol. 2025 ;16 1717541

Unveiling the myxofibrosarcoma tumor microenvironment: implications for immunotherapy.

Cecilia Profumo, Massimiliano Grassi, Valentina Rigo, Matteo Mascherini, Paola Monti, Giorgia Arcovito, Giorgia Anselmi, Laura Damele, Giorgia Timon, Danila Comandini, Michela Croce.

  Myxofibrosarcoma (MFS) is a rare and aggressive soft tissue sarcoma characterized by high genomic instability, resulting in high local recurrence rates and limited effective therapeutic options in advanced stages. Recent progress in cancer immunology research has encouraged investigation into the Tumor Microenvironment (TME) of sarcomas, including MFS, to identify immune-related biomarkers of prognostic and therapeutic relevance. Although data remain limited in MFS, existing evidence suggests a heterogeneous immune landscape, including: i) variable expression of immune checkpoint molecules such as Programmed Cell Death Protein 1 (PD-1) and Programmed Death-Ligand 1 (PD-L1), ii) presence of tumor-infiltrating lymphocytes, iii) alterations in antigen presentation pathways, and iv) a pronounced angiogenic signature. These findings underscore the potential role of immune biomarkers for patients' clinical stratification and the consequent possibility of developing new immunotherapeutic strategies. This review will focus on the cellular and molecular architecture of immune infiltration, vascular remodeling, and lymphoid neogenesis, assessing their prognostic and predictive value as potential biomarkers. Finally, we will present ongoing clinical trials aimed at modulating the immune-vascular niche to inform innovative therapeutic strategies for this challenging sarcoma subtype.

Keywords:  biomarkers; immune checkpoint inhibitors; immunotherapy; myxofibrosarcoma; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1717541
bioRxiv. 2025 Dec 06. pii: 2025.12.04.692214. [Epub ahead of print]

Bispecific T cell engagers control solid tumors through clonal replacement and IL2-driven effector differentiation of CD8 T cells.

Matthias Obenaus, Clara L Poupault, Christopher S McGinnis, Céline Prange, Hua Jiang, Leon L Su, Xiaojing Chen, Zhuang Miao, Joseph J Muldoon, Winnie Yao, Deepa Waghray, Qinli Sun, Justin Eyquem, Rogelio A Hernández-López, Ansuman T Satpathy, Julien Sage, K Christopher Garcia.

Bispecific T cell engagers (TCEs) often exhibit limited efficacy in solid tumors, in part due to immunosuppressive cues in the tumor microenvironment and low expression of targetable tumor antigens. Therapeutic strategies to improve TCE target sensitivity and enhance T cell effector functions therefore have significant translational potential. Here, we engineered TCEs that induce T cell activation in vitro against the low-abundance target antigens, TRP2/K b and DLL3. Despite in vitro activity in these models, TCE monotherapy showed limited control of tumor growth in immunocompetent mice. Leveraging this in vivo model of TCE treatment failure, we discovered that co-treatment with TCE and a CD25-biased Interleukin-2 (IL2) rescues anti-tumor activity. Further, multimodal single-cell transcriptomic and immune repertoire analyses revealed that TCE-IL2 combination therapy controlled tumors by recruiting and activating new CD8 + T cells into the tumor microenvironment. These findings demonstrate that TCE-mediated anti-tumor responses function through a CD8 + T cell clonal replacement mechanism that can be augmented by cytokine therapy.

DOI: https://doi.org/10.64898/2025.12.04.692214
Front Immunol. 2025 ;16 1692864

Targeting PDPN enhances antitumor T-cell activity by disrupting β-catenin-mediated PD-L1 expression in melanoma.

Chunyan Feng, Yueyue Liu, Xinyue Zhong, Zhenzhen Wei, Hongjing Cui, Jianfeng Yi.

   Introduction: Melanoma is a highly immunogenic and aggressive malignancy characterized by pronounced intratumoral lymphocytic infiltration and significant responsiveness to immunotherapeutic interventions. The oncogenic glycoprotein podoplanin (PDPN) is commonly overexpressed in various cancer types, where it facilitates metastatic dissemination through interactions with CLEC-2 on platelets and other stromal cells, thereby contributing to stromal immunosuppression. Although the protumoral roles of PDPN are well documented, its precise mechanistic contributions to immune evasion in melanoma remain only partly defined and require further elucidation.
Methods: To clarify the immunological role of PDPN in melanoma, multiplex immunofluorescence staining was performed on human tissue microarrays, and bioinformatic analyses were conducted to determine the associations of PDPN with PD-L1 expression and CD8+ T cell infiltration. The therapeutic efficacy and underlying mechanisms of the PDPN-targeting inhibitory peptide CY12-RP2 were systematically evaluated using flow cytometry, Western blotting, ELISA, and in vivo studies in both immunodeficient and immunocompetent mouse models. These comprehensive analyses demonstrated that targeting PDPN with CY12-RP2 can reestablish antitumor immunity.
Results: Multi-omics analyses indicated that PDPN expression is highly correlated with immune checkpoint markers, most notably PD-L1 (r = 0.504, p < 0.001), and displays an inverse relationship with the infiltration of intratumoral cytotoxic immune cells. Single-cell and spatial transcriptomic profiling revealed that PDPN supports the exclusion of CD8+ T cells and enhances the prevalence of immunosuppressive cell populations. CY12-RP2 resulted in a 60.6% reduction in tumor growth in immunocompetent murine models and reversed immune evasion by attenuating PDPN-dependent, β-catenin-mediated upregulation of PD-L1. Treatment with CY12-RP2 broadly activated antitumor immune responses, as evidenced by increased intratumoral infiltration of CD8+ T cells, elevated granzyme B production by CD8+ T cells, and enhanced secretion of pro-inflammatory cytokines (IFN-γ, TNF-α, and IL-1β). Depletion experiments confirmed that the antitumor efficacy of CY12-RP2 was entirely dependent on CD8+ T cells, establishing a CD8+ T cell-dependent mechanism of action.
Discussion: These findings identify PDPN as a critical driver of immune evasion in melanoma via b-catenin-mediated PD-L1 upregulation. Inhibitory targeting of PDPN with CY12-RP2 represents a promising therapeutic approach capable of disrupting this immunosuppressive pathway and reversing tumor immune escape.

Keywords:  CD8 lymphocytes+; PD-L1; Wnt/β-catenin; immunotherapy; podoplanin

DOI:  https://doi.org/10.3389/fimmu.2025.1692864
Mol Ther. 2026 Jan 21. pii: S1525-0016(26)00022-5. [Epub ahead of print]

Phase I study of autologous T cells bearing fully human chimeric antigen receptors targeting mesothelin in mesothelin-expressing cancers.

Julie S Barber-Rotenberg, Andrew R Haas, Charu Aggarwal, Mark O'Hara, Elizabeth Hexner, Edward Pequignot, Emily Dowd, Sonia Ndeupen, Elina Thai, Fang Chen, Bike Su Oner, Cory Czuczman, Vanessa E Gonzalez, Joseph A Fraietta, Wei-Ting Hwang, Anne Chew, Julie K Jadlowsky, Amy Marshall, Kim-Marie Shea, Yan Jiang, Angela Cosey, Regina Ferthio, Bruce L Levine, Gabriela Plesa, Don L Siegel, Regina M Young, Neil C Sheppard, Steven M Albelda, Carl H June, Janos L Tanyi.

This phase I study evaluated the safety and feasibility of fully humanized huCART-meso T cells in patients with lung adenocarcinoma, ovarian cancer, and mesothelioma. huCART-meso cells were administered intravenously, intrapleurally, and/or intraperitoneally with or without lymphodepletion. The huCART-meso cells are autologous T cells engineered to express a fully human extracellular single-chain antibody with mesothelin specificity and 4-1BB/TCRζ intracellular signaling domains. All patients (n=20) received a dose of 1-3 x 107 CAR+ cells/m2 (1 patient with lung adenocarcinoma, 5 patients with mesothelioma, and 14 patients with ovarian cancer). Peak expansion was observed within the first 14 days and huCART-meso cells were detectable in 16/20 patients at Day 21 and in 5 patients at 12 months. With one patient showing detectable cells for over two years. The most common serious adverse event was cytokine release syndrome (7/20 patients, 35%). The best overall response was stable disease (12/20 patients, 60%) with a maximum reduction in target tumor volume of 41%. The median overall survival was 26.1 weeks and the median progression-free survival was 12.3 weeks. These results establish the feasibility, safety, and preliminary efficacy of huCART-meso therapy, providing a rationale for future trials, ideally in combination with other therapies.

DOI: https://doi.org/10.1016/j.ymthe.2026.01.021
Med Sci (Basel). 2025 Dec 31. pii: 18. [Epub ahead of print]14(1):

UniTope & TraCR: A Universal Tool to Tag, Enrich, and Track TCR-T Cells and Therapeutic Proteins.

Kanuj Mishra, Barbara Lösch, Dolores J Schendel.

   BACKGROUND: Adoptive cell therapy using genetically engineered recombinant T cell receptors (rTCRs) expressed in T cells (TCR-T cell therapy) provides precision targeting of cancer cells expressing tumor-associated or tumor-specific antigens recognized by the rTCRs. Standardized analytical tools are lacking to easily quantify receptor expression.
METHODS: To overcome this hindrance, a universal tagging system (UniTope & TraCR) was designed consisting of a minimal peptide epitope (UniTope) inserted into the constant region of the rTCR α or β chain and a high-affinity monoclonal antibody (TraCR) specific to this tag. Detailed biophysical, biochemical, and functional assays were performed to evaluate rTCR expression, folding, pairing, and antigen recognition, as well as antibody performance, using the UniTope & TraCR System.
RESULTS: Tagged rTCRs were stably expressed in human T cells with surface densities comparable to untagged rTCRs. The TraCR antibody bound UniTope with nanomolar affinity and no detectable cross-reactivity was observed for endogenous proteins expressed by human cells of diverse origin, importantly, including T cells of the natural T cell repertoires of multiple human donors. Functional assays confirmed that UniTope-tagged rTCRs preserved their antigen-specific cytokine secretion and cytolytic activity upon antigen-specific stimulation. The UniTope & TraCR System enabled robust detection of rTCR-expressing T cells by flow cytometry, and rTCR protein expression by Western blot or immunoprecipitation, supporting the quantitative assessment of receptor copy number and structural integrity.
CONCLUSIONS: The UniTope & TraCR System provides a modular, construct-agnostic platform for monitoring engineered rTCRs, integrated into TCR-T cell therapies currently in development.

Keywords:  T cell receptor; adoptive cell therapy; epitope tag; immunotherapy analytics; quality control; universal antibody

DOI:  https://doi.org/10.3390/medsci14010018
Front Immunol. 2025 ;16 1638585

VHH-based CAR-T cells targeting Claudin 18.2 show high efficacy in pancreatic cancer models.

Ying Xing, Gangqiang Shi, Zhengli Li, Xiancheng Liu, Linghu Nie, Yu Zhang, Yiqin Song, Shilin Sun, Mike K S Chan, Michelle B F Wong, Krista Casazza, Jonathan R T Lakey, Yuping Chen, Xuekai Zhu, Yunfeng Feng.

   Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers, with a 5-year survival rate below 10%, largely due to late-stage diagnosis and the limited effectiveness of conventional therapies such as surgery, chemotherapy, and radiation. Claudin 18.2 (CLDN18.2)has emerged as a promising target for PDAC. While single-chain variable fragment (scFv)-based CAR-T cells targeting CLDN18.2 have demonstrated therapeutic potential, CAR-T cells engineered with variable heavy-chain-only domains (VHH) exhibit superior efficacy, highlighting the advantages of VHH-based constructs in targeting this antigen. However, the therapeutic efficacy of anti-CLDN18.2 VHH-CAR-T cells remains to be fully elucidated, as previous studies have not comprehensively characterized in vivo performance or mechanistic advantages over scFv-based counterparts.
Methods: To characterize the therapeutic potential of anti-CLDN18.2 VHHs, we employed phage display technology to screen a VHH library, resulting in the identification of three positive clones. These candidates were further evaluated and ranked based on binding affinity and multi-round cytotoxicity in Chimeric antigen receptor T (CAR-T) cell models. To reduce immunogenicity, the lead VHH was humanized. VHH-CAR-T cells incorporating this humanized domain were assessed through in vitro assays measuring cytokine secretion and target cell lysis, followed by in vivo studies to evaluate antitumor efficacy in relevant xenograft models.
Results: High-affinity anti-CLDN18.2 VHHs from phage libraries and engineered CAR-T cells using HM2, a humanized VHH, as the antigen-binding domain were successfully identified. Notably, HM2-CAR-T cells demonstrated potent and sustained cytokine secretion and cytotoxic activity against CLDN18.2-expressing tumor cells in vitro. More importantly, these VHH-based CAR-T cells achieved significant antitumor efficacy in vivo, underscoring the translational potential of VHH-CAR constructs as a next-generation therapeutic platform with enhanced performance and reduced immunogenicity compared to conventional scFv-based designs.
Conclusion: This study establishes an effective framework for developing CLDN18.2-specific VHHs and demonstrates their successful integration into CAR-T cell therapy. The humanized HM2-CAR-T cells not only maintain high antigen specificity but also exhibit strong effector functions and pronounced antitumor activity in preclinical models. These findings support the clinical promise of VHH-based CAR-T cells as a next-generation immunotherapy for CLDN18.2-expressing malignancies, particularly PDAC, where effective treatment options remain limited.

Keywords:  CAR-T cell; CLDN18.2; PDCA; VHH; cellular therapy

DOI:  https://doi.org/10.3389/fimmu.2025.1638585
Transfus Med Hemother. 2025 Nov 25.

Improved Antitumor Activity of Interleukin-12-Secreting Chimeric Antigen Receptor T Cells Targeting CD176 across Different Carcinomas.

Melina Umland, Anna Christina Dragon, Luca Marie Beermann, Agnes Bonifacius, Patrik Kehler, Johanna Gellert, Rainer Blasczyk, Hinrich Abken, Axel Schambach, Michael Hudecek, Britta Eiz-Vesper.

   Introduction: Effective therapeutic options for advanced solid tumors remain severely limited, causing high fatality rates especially after metastasis. The carbohydrate structure CD176 has been identified as a promising target for precise immunotherapy in multiple carcinomas, as it is present in about 90% of carcinomas but unavailable for binding on healthy tissue. Here, we report the development of CD176-specific 4th-generation chimeric antigen receptor T cells (CAR-Ts), also known as T cells redirected for antigen-unrestricted cytokine-initiated killing (TRUCKs). To address the immunosuppressive tumor microenvironment (TME) and the heterogeneous antigen expression of solid tumors, which limit the efficacy of CAR-Ts, they were endowed with NFAT-inducible interleukin-12 (iIL12) release to improve pro-inflammatory autocrine and paracrine effects.
Methods: The CD176-iIL12-TRUCK construct was tested for target specificity in a reporter cell assay using a JE6-1-derived reporter cell line. Afterward, CD176-iIL12-TRUCKs were manufactured using primary CD8+ T cells. The influence of iIL12 on functionality of CD176-iIL12-TRUCKs, including T-cell activation levels, cytotoxic capacity, and recruitment of bystander immune cells, was evaluated following cocultures with CD176+ cell lines from different carcinomas.
Results: Upon recognition of CD176+ cancer cell lines, CD176-iIL12-TRUCKs specifically released pro-inflammatory mediators (interferon-γ, tumor necrosis factor-α) and showed an increased activation marker expression (CD25, CD69). Using both a 7-AAD-based viability assay and an impedance-based cytotoxicity assay, elimination of CD176+ cell lines from different tumor entities by CD176-iIL12-TRUCKs was shown. Additionally, iIL12 released by CD176-iIL12-TRUCKs led to recruitment of monocyte and NK cell lines in a chemotaxis chamber assay.
Discussion/Conclusion: Overall, the IL-12 release substantially improved effector functionality against CD176+ cells but not CD176- cells, indicating efficacy while maintaining specificity. Thus, CD176-iIL12-TRUCKs, with their potent antitumor efficacy and TME modulation potential, are a promising treatment option for patients with a variety of advanced solid tumors.

Keywords:  CD176; Chimeric antigen receptor T cells; Interleukin-12; Solid tumors; T cell redirected for antigen-unrestricted cytokine-initiated killing

DOI:  https://doi.org/10.1159/000549632
Front Oncol. 2025 ;15 1704359

Tracking temporal shifts of peripheral blood NLR, PLR, and ALB: a prognostic tool for PD-1 inhibitor efficacy in advanced malignant melanoma.

Yushu Deng, Yikai Han, Xiangrui Meng, Jiaxin Pei, Mengmeng Yang, Ziyi Xiao, Feng Wang, Taiying Lu.

   Objective: PD-1 monoclonal antibodies are cornerstone therapies for advanced malignant melanoma, yet treatment response varies greatly between patients. This study investigated temporal changes in peripheral blood inflammatory and nutritional parameters during PD-1 therapy, examined their associations with clinical outcomes, and identified prognostic biomarkers.
Methods: A retrospective analysis was conducted on 99 patients with advanced malignant melanoma who received PD-1 monoclonal antibody treatment at the First Affiliated Hospital of Zhengzhou University (January 2019-September 2024). Imaging evaluations (CT/MRI, with PET-CT for suspected distant metastasis) were performed at baseline (T0, before treatment), the end of the 2nd cycle (T2), and the end of the 4th cycle (T4) to assess treatment response per the immune-related Response Evaluation Criteria in Solid Tumors (irRECIST).After four treatment cycles, patients were stratified into a clinical benefit group (complete response [CR] + partial response [PR] + stable disease [SD], n=68) and a non-benefit group (progressive disease [PD], n=31) based on the immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). Peripheral blood samples were collected at five time points: baseline (T0), post-first cycle (T1), post-second cycle (T2), post-third cycle (T3), and post-fourth cycle (T4). Dynamic changes in neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), serum albumin (ALB), and prognostic nutritional index (PNI) were compared between groups. Line graphs and box plots were used to visualize indicator trends, while logistic regression and receiver operating characteristic (ROC) curves were applied to evaluate prognostic value.
Results: Non-benefit patients showed NLR peaks at T2 and PLR peaks at T1, while benefit patients had stable levels. ALB and PNI were higher and stable in the benefit group (P<0.05). A model combining T1PLR, T1ALB, and T2NLR achieved an AUC of 0.89 (sensitivity 0.90, specificity 0.79).
Conclusion: Dynamic monitoring of peripheral blood NLR, PLR, and ALB provides critical insights for predicting PD-1 immunotherapy efficacy in patients with advanced malignant melanoma. These indicators hold promise as potential clinical biomarkers to guide the development of individualized treatment strategies.

Keywords:  hematological markers; immunotherapy; malignant melanoma; nutritional markers; prognostic role

DOI:  https://doi.org/10.3389/fonc.2025.1704359
Cancer Res. 2026 Jan 22.

Intratumoral Lactobacillus johnsonii Enhances Sensitivity to PD-1 Blockade by Inducing CD8+ T Cell Expansion in Hepatocellular Carcinoma.

Qianshi Liu, Yiqiang Liu, Yue Zhou, Liang Liang, Yejian Wan, Ying Wang, Ting Huang, Ling Zhong, Zhaoshen Li, Tao Luo, Ming Zhao, Zhe-Xuan Li, Yu-Cong Li, Hai-Tao Lan, Hong Wu, Chuan Xu, Jie Chen.

While surgical resection is an effective intervention for early-stage hepatocellular carcinoma (HCC), postoperative recurrence remains a major clinical hurdle. Delving into the mechanisms underlying relapse and pinpointing potential therapeutic targets are imperative for improving HCC patient outcomes. By comparing the microbiota composition in patients with early-relapsing and non-relapsing HCC, we identified that Lactobacillus was enriched in relapse-free HCC patients, serving as an independent prognostic predictor of disease-free survival. Higher levels of intratumoral Lactobacillus johnsonii (L. johnsonii) correlated with an increased abundance of IFN-γ+PD-1+CD8+ T cells. Single-cell RNA sequencing, transcriptomic profiling of intratumoral CD45+ immune cells, and in vitro functional assays demonstrated that L. johnsonii preferentially enhanced this cytotoxic-exhausted T cell population. Nicotinic acid (NA) served as a key metabolite derived from L. johnsonii that expanded IFN-γ+PD-1+CD8+ T cells and upregulated effector (GZMB) and exhaustion (CTLA-4) markers. Mechanistically, both L. johnsonii and NA activated the NF-κB pathway, leading to increased IFN-γ production and upregulation of the transcription factor NR4A2, which in turn sustained PD-1 expression on CD8+ T cells. Combining L. johnsonii or NA with anti-PD-1 therapy synergistically inhibited tumor relapse and tumor growth in immunocompetent or humanized mice. Crucially, the anti-tumor efficacy of L. johnsonii was CD8+ T cell-dependent, as depletion abolished its activity. This work unveils a mechanism by which L. johnsonii and its metabolite NA enrich intratumoral IFN-γ+PD-1+CD8+ T cells, thereby reshaping the immune microenvironment to potentiate immunotherapy efficacy and suppress HCC recurrence.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0346
Med Oncol. 2026 Jan 19. 43(2): 120

Targeting thymidylate synthase enhances CD8 + T-cell infiltration and inhibits tumor growth in cervical cancer.

Yongyan Pei, Zheng Zhong, Hongliang Li, Yuanchang Tan, Hua Cao.

  Cervical cancer (CESC) presents a significant clinical challenge, primarily due to an incomplete understanding of the immunometabolic crosstalk within the tumor microenvironment (TME) and the lack of reliable biomarkers for immunotherapy stratification. Thymidylate synthase (TYMS), a pivotal enzyme in nucleotide synthesis, has been implicated in tumor progression, but its role as an immunometabolic regulator in CESC remains unexplored. Through an integrative approach combining single-cell RNA sequencing (scRNA-seq) of 47,589 cells, bulk transcriptomics, functional assays, and in vivo modeling, we delineated the multifaceted functions of TYMS. scRNA-seq analysis revealed a dynamic shift from CD4 + to exhausted CD8 + T-cell dominance during progression, orchestrated by specific ligand-receptor interactions like PTPRC-MRC1. A robust T cell-associated prognostic signature comprising TYMS, MYO6, SPINT1 and ESD was developed, effectively stratifying patients into distinct risk groups with differential tumor stemness, immune infiltration, and response to immunotherapy. Mechanistically, TYMS silencing promoted tumor stemness, migration, and invasion in vitro via targeting miR-197-3p. Crucially, in immunocompetent micemodel, TYMS knockdown accelerated tumor growth and potently suppressed CD8 + T-cell infiltration, demonstrating its role in promoting immune evasion. Conversely, TYMS overexpression suppressed tumorigenesis. Molecular docking identified Deoxyuridine Monophosphate as a high-affinity inhibitor of TYMS. Our findings demonstrate that targeting thymidylate synthase enhances CD8 + T-cell infiltration and inhibits tumor growth in cervical cancer, establishing TYMS as a promising therapeutic target.

Keywords:  Cervical cancer; Immunotherapy; Molecular docking; Prognostic signature; Thymidylate synthase; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12032-026-03250-5
Nat Immunol. 2026 Jan 19.

Unraveling CD8 lineage decisions reveals that functionally distinct CD8+ T cells are selected by different MHC-I thymic peptides.

Miho Shinzawa, Nicole Ramos, Khanh Bui, William Hajjar, Assiatu Crossman, Xiongfong Chen, Margaret Cam, Yousuke Takahama, Alfred Singer.

Thymocytes signaled by T cell antigen receptors to undergo positive selection acquire different functional fates while migrating through the thymus, but how this occurs remains uncertain. We now report that encoding CD8 co-receptors in both Cd4 and Cd8 gene loci modulates major histocompatibility complex (MHC-I) class I T cell antigen receptor signaling duration to generate all potential CD8+ T cell subsets. Strikingly, such mice revealed that functionally different CD8+ T cells are selected by different MHC-I thymic peptides. Thymocytes signaled by β5t-peptides produced by thymoproteasomes exclusively expressed in the thymic cortex invariably become cytotoxic CD8+ T cells indicating their signaling ceases when thymocytes leave the cortex; whereas thymocytes signaled by nonβ5t-peptides expressed throughout the thymus become either helper or innate memory CD8+ T cells because their signaling persists or recurs outside the cortex. Thus, it is because of their different thymic distributions that different MHC-I peptides select functionally different CD8+ T cells, integrating peptide specificity and CD8+ T cell function during positive selection and thymocyte migration.

DOI: https://doi.org/10.1038/s41590-025-02411-4
Adv Sci (Weinh). 2026 Jan 20. e21623

Engineered CAR-NKT Extracellular Vesicles Suppress Tumor Progression and Enhance Antitumor Immunity.

Xiaopei Hao, Chengming Qu, Yanzhao Zhou, Xiaoqian Wang, Xiangjun Qian, Xun Chen, Feng Han, Xiaokai Zhang, Yiyi Ji, Han Li, ChengWei Ju, Peng Xia, Weiwei Tang, Hao Zhuang, Jinxue Zhou.

  Chimeric antigen receptor-engineered natural killer T (CAR-NKT) cell therapy represents a promising and innovative strategy in cancer immunotherapy, but is limited by acute toxicity and adverse effects, restricting broader clinical application despite durable responses. In this study, a novel nanobody targeting TM4SF1 is developed, which replaced the conventional single-chain variable fragment (scFv) in the design of CARTM4SF1-NKT cells. Moreover, CARTM4SF1-extracellular vesicles (EVs) therapy as an optimized alternative to direct CAR-NKT cell administration is introduced. Compared with conventional CARTM4SF1 engineered cells, CARTM4SF1-EVs demonstrated superior antitumor efficacy while significantly reducing toxicity. This findings revealed that CARTM4SF1-EVs selectively targeted TM4SF1-expressing tumor cells in both in vitro and in vivo models. In hepatocellular carcinoma (HCC) mouse models, CARTM4SF1-EVs induced immunogenic cell death (ICD) and effectively suppressed tumor growth and metastasis. The therapeutic efficacy of CARTM4SF1-EVs is primarily attributed to their ability to remodel the immunosuppressive tumor microenvironment (TME), notably by enhancing CD8⁺ T cell activity and eliciting robust antitumor immune responses. Furthermore, CARTM4SF1-EVs synergized with Immune Checkpoint Blockade (ICB) therapy, leading to durable antitumor immune memory. Collectively, these findings establish CARTM4SF1-EVs therapy as a safe and effective strategy for targeted cancer immunotherapy, underscoring its potential for clinical application.

Keywords:  CAR‐NKT; TM4SF1 nanobody; cancer therapy; extracellular vesicles; immunotherapy

DOI:  https://doi.org/10.1002/advs.202521623