bims-tuinly 2026-03-29 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2026–03–29
seventeen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

From Immunobiology to Clinical Application: Tumor-Infiltrating Lymphocytes in Melanoma.
High CD73 Expression Is Associated with Poor Prognosis in Biliary Tract Cancer Through Reduced Stromal Tumor-Infiltrating Lymphocytes.
From counting to clustering: AI-defined "diffuse" vs. "focal" spatial patterns as the new precision biomarker for triple-negative breast cancer.
Targeting T-Cells for Cancer Treatment: Current Clinical Strategies and Challenges.
Prostate-Specific Membrane Antigen (PSMA): A Potential Theranostic Biomarker in Breast Cancer.
CTL-NK Signature Based on Immune Gene Profiling and IHC Predicts Clinical Outcomes in Triple-Negative Breast Cancer.
Liver-directed AAV-IL-10 therapy enhances CD8+ T cell-mediated immunity against hepatocellular carcinoma.
TOPK Suppresses the CD8+ T Cell Antitumor Immunity via Modulation of IRF5 Expression.
Multi-Omics Profiling Uncovers Predictive Factors for Tumor-Infiltrating Lymphocyte Therapy in Ovarian Cancer.
Exploratory analysis of stromal and peritumoural tumour-infiltrating lymphocytes (tils) in malignant parotid gland tumours: associations with clinicopathological factors and survival.
Salvage Metastasectomy After Adoptive Cell Transfer for Melanoma: Long-Term Updates.
ZFP148 is a transcriptional repressor of cytolytic effector CD8+ T cell differentiation.
Invariant Natural Killer T Cells in Cancer Immunotherapy: Lipid-Based Modulation, Nanotechnology, and Translational Advances.
Re-Tooling of γδ T Cells for Cancer Immunotherapy Using Advanced Manufacturing and Genetic Engineering.
Advancing adoptive cellular immunotherapy via Notch-based ex vivo T cell development platforms.
Integrative Single-Cell and Spatial Transcriptomic Analysis Reveals MAIT Cell Dysfunction in Relapsed HCC.
Integration of dual-energy CT parameters and radiomics features for non-invasive prediction of α-SMA and CD8 + T cell in non-small cell lung cancer.

J Pers Med. 2026 Mar 03. pii: 147. [Epub ahead of print]16(3):

From Immunobiology to Clinical Application: Tumor-Infiltrating Lymphocytes in Melanoma.

Mislav Mokos, Mirna Šitum.

  Background: Tumor-infiltrating lymphocytes (TILs) play a key role in the immune response against melanoma. They act as both markers of an active tumor environment and as treatments in adoptive cell therapy. This narrative review covers what is currently known about TIL biology, their prognostic and predictive value, and the use of TIL-based adoptive cell therapy (TIL-ACT) in advanced melanoma. Methods: We searched PubMed/MEDLINE, Web of Science and clinicaltrials.gov through January 2026 using terms related to melanoma, TILs, adoptive cell therapy, immune checkpoint inhibitors, neoantigens, T-cell receptor clonality, and spatial transcriptomics. We included original research, major clinical trials, translational studies and key reviews. Results: Melanoma often has many neoantigens, which leads to a high number of tumor-resident TILs. These TILs, their arrangement, and their interactions with myeloid cells influence how well they fight tumors. Features of TILs seen under the microscope and through other tests can help predict patient outcomes, even before treatment. Studies show that TIL-ACT leads to objective responses in about 30-50% of patients whose melanoma did not respond to immune checkpoint inhibitors. Some patients achieve lasting complete remissions, though the treatment can cause significant, mostly short-term side effects from lymphodepletion and interleukin-2. New research points to factors related to the patient, tumor, and TIL product that affect treatment success, supporting the use of biomarkers and combination strategies. Conclusions: TIL-based adoptive cell therapy is now a promising, personalized treatment for advanced melanoma after anti-PD-1 therapy has failed. Future studies should focus on identifying reliable biomarkers, improving TIL products, combining therapies to change the tumor environment, and making manufacturing more efficient to ensure more patients can safely access TIL therapy.

Keywords:  adoptive cell therapy; biomarkers; immune checkpoint inhibitors; immunotherapy; lifileucel; melanoma; personalized medicine; tumor microenvironment; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3390/jpm16030147
Cancers (Basel). 2026 Mar 18. pii: 975. [Epub ahead of print]18(6):

High CD73 Expression Is Associated with Poor Prognosis in Biliary Tract Cancer Through Reduced Stromal Tumor-Infiltrating Lymphocytes.

Shoya Shiratori, Kazumichi Kawakubo, Kanako C Hatanaka, Takuma Kobayashi, Teppei Konishi, Yoshiki Shinomiya, Soichiro Oda, Shunichiro Nozawa, Hiroki Yonemura, Ryo Sugiura, Kazuaki Harada, Yoshitsugu Nakanishi, Takehiro Noji, Shinya Tanaka, Satoshi Hirano, Masaki Kuwatani, Yutaka Hatanaka, Naoya Sakamoto.

  Background: Biliary tract cancer (BTC) is an aggressive malignancy with limited therapeutic options and a poor prognosis. CD73 is upregulated under hypoxic conditions and promotes tumor progression. However, its clinical role in BTC and interaction with tumor-infiltrating lymphocytes (TILs) remain unclear. This study aimed to elucidate the association between CD73 expression and prognosis in BTC, as well as its impact on the tumor microenvironment (TME) and TILs. Methods: This retrospective study included 100 patients who underwent curative BTC surgery at Hokkaido University Hospital between 2018 and 2023. Formalin-fixed tumor specimens were analyzed using DeepPathFinder™ (biomy Inc., Tokyo, Japan), an AI-based digital pathology platform enabling objective quantification of CD73 expression and lymphocyte infiltration within tumoral (T) and stromal (S) compartments. Immunohistochemistry for CD3, CD8, Foxp3, and CD163 was used to identify T-cell subsets and macrophages. Associations between CD73, TIL subsets, and overall survival (OS) were assessed using the Kaplan-Meier, Cox regression, and Spearman correlation analyses. Results: High T-CD73 expression was associated with shorter OS (hazard ratio [HR] = 1.97, p = 0.041), whereas S-CD73 showed no prognostic relevance. Conversely, high S-TIL density was correlated with improved survival (HR = 0.49, p = 0.032). T-CD73 expression was negatively correlated with stromal CD3+ and CD8+ T-cell densities, indicating selective suppression of stromal cytotoxic T-lymphocyte (CTL) infiltration. No significant correlations were observed between Foxp3+ T cells and CD163+ M2 macrophages. Conclusions: CD73 upregulation in tumor cells impairs stromal CTL and TIL activity, leading to a poor prognosis. Spatial distribution, rather than total TIL number, better reflects effective anti-tumor immunity.

Keywords:  CD73; biliary tract cancer; digital pathology; infiltrating lymphocyte; stroma

DOI:  https://doi.org/10.3390/cancers18060975
Front Immunol. 2026 ;17 1796137

From counting to clustering: AI-defined "diffuse" vs. "focal" spatial patterns as the new precision biomarker for triple-negative breast cancer.

Liyun Cai, Pengping Li.



Keywords:  artificial intelligence; precision biomarker; spatial clustering; triple-negative breast cancer; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3389/fimmu.2026.1796137
Biomedicines. 2026 Mar 13. pii: 654. [Epub ahead of print]14(3):

Targeting T-Cells for Cancer Treatment: Current Clinical Strategies and Challenges.

Anand Rotte, Mentor Sopjani, Madhuri Bhandaru.

  Modulation of immune response to target tumor cells has been shown to be a successful strategy for cancer treatment. Over the past years immunotherapy has been integrated into cancer treatment and PD-1 blockers have become the backbone of treatment regimens for multiple cancer types. Several classes of immunotherapies, such as immune checkpoint blockers, bispecific antibodies, chimeric antigen receptor (CAR) T-cells, and tumor-infiltrating lymphocytes (TILs), were approved by the US FDA in the last decade and many more are in clinical trials. Research on redirecting effector T-cells to treat cancer has been aimed at addressing the limited responses in solid tumors, emergence of resistance, treatment-limiting adverse events and logistical challenges. Bispecific immune checkpoint blockers, developed to simplify the combination therapies; bispecific T-cell engagers, developed to connect the effector T-cells with tumor cells; and the next generation of CAR T-cells and the next generation of TIL therapies, developed to improve efficacy in solid tumors, are currently under clinical evaluation. This narrative review aims to summarize the current status of T-cell-directed immunotherapy, describing the brief history of development, clinical success, challenges and latest advancements that are under clinical evaluation. Evolution of monoclonal antibodies to bispecific antibodies and bispecific T-cell engagers, the latest advances in adoptive cell therapies, including the optimization of CAR T-cells for solid tumors, allogenic, universal CAR T-cells and in vivo CAR T-cell therapies are discussed in the review along with the key challenges of the therapies, such as primary and acquired resistance, limited efficacy in solid tumors, manufacturing and logistical challenges, and treatment-related toxicities.

Keywords:  BiTEs; CAR T-cells and TIL therapy; PD-1; effector T-cells; immunotherapy

DOI:  https://doi.org/10.3390/biomedicines14030654
Biomedicines. 2026 Mar 11. pii: 628. [Epub ahead of print]14(3):

Prostate-Specific Membrane Antigen (PSMA): A Potential Theranostic Biomarker in Breast Cancer.

Alessandra Virga, Flavia Foca, Stefania Cortecchia, Francesca Poli, Paola Caroli, Federica Matteucci, Roberta Maltoni, Massimiliano Mazza, Fabio Nicolini, Paola Ulivi, Giovanni Paganelli, Maurizio Puccetti, Sara Bravaccini.

  Background: Subtype classification for breast cancer (BC) patients is important for risk-stratification. Unfortunately, this parameter is not always able to discriminate between high- and low-risk diseases. Glutamate Carboxypeptidase-II (GCPII), also known as prostate-specific membrane antigen (PSMA), could be an important biomarker of aggressiveness, given that it has been reported to be expressed in BC tumor cells and even more in endothelial cells of tumor vessels. Methods: We analyzed 22 Luminal A, 47 Luminal B, 9 HER2-positive (HER2+), and 23 triple-negative (TN) BC to assess whether PSMA, Ki67 expression, and tumor-infiltrating lymphocytes (TILs) were different in BC subtypes. Results: Median PSMA and Ki67 values were significantly higher in TNBC than in Luminal A and B tumors. We saw a correlation between PSMA and Ki67 expression, especially in HER2+ tumors (p = 0.035), while an inverse correlation between PSMA and TILs was observed in Luminal A (p = 0.028). Conclusions: Our results suggest that PSMA could be used as a biomarker in BC, given that it is highly expressed in more aggressive tumors. These findings open the way to a clinical investigation for the possible use of PSMA as a theranostic biomarker in BC patients with PSMA positive PET scan.

Keywords:  Ki67 and PSMA PET/CT; PSMA expression; TILs; breast cancer; theranostic biomarker

DOI:  https://doi.org/10.3390/biomedicines14030628
Cancer Invest. 2026 Mar 25. 1-18

CTL-NK Signature Based on Immune Gene Profiling and IHC Predicts Clinical Outcomes in Triple-Negative Breast Cancer.

Ahmed J Alfahdawi, Ali Mohammed Sameen, Ashjan Mohammed Hussien, Noor T Al-Bayatee, Tareq Hafdi Abdtawfeeq, Rashied M Rashied, Maysam N Ahmed, Majid S Jabir.

   AIM: Triple-negative breast cancer (TNBC) lacks targeted therapies and demonstrates heterogeneous outcomes. Tumor-infiltrating lymphocytes (TILs) are candidate prognostic biomarkers that reflect the tumor immune microenvironment. This study evaluated the prognostic value of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, with emphasis on granulysin (GNLY) and granzyme B (GZMB), in TNBC.
MATERIALS & METHODS: We combined NanoString immune gene profiling with whole-slide immunohistochemistry (IHC) in a TNBC cohort (n = 155). Quantitative and spatial analyses were performed to assess CTL and NK cell infiltration and their associations with clinicopathological features and survival outcomes.
RESULTS: High TIL density (≥10%) and elevated CTL-NK scores (≥2) correlated with lower tumor stage, absence of lymphovascular invasion (LVI), and favorable immune subset ratios (all p < 0.05). In multivariable analysis, absence of LVI, high CD4+ and CD8+ infiltration, and CTL-NK score ≥2 independently predicted improved disease-free survival (DFS; hazard ratio [HR] range 0.45-0.62, all p < 0.05). CD4+ infiltration demonstrated the strongest prognostic effect, while CD8+ infiltration and the CTL-NK score also conferred independent benefit.
CONCLUSION: Quantitative and spatial assessment of CTL and NK infiltration provides independent prognostic information in TNBC. The CTL-NK score can be integrated into routine pathology and may refine risk stratification, supporting personalized immunotherapy strategies.

Keywords:  Cytotoxic T lymphocytes; Immune microenvironment; Immunohistochemistry; Natural killer cells; Triple-negative breast cancer; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1080/07357907.2026.2644899
J Immunother Cancer. 2026 Mar 27. pii: e012460. [Epub ahead of print]14(3):

Liver-directed AAV-IL-10 therapy enhances CD8+ T cell-mediated immunity against hepatocellular carcinoma.

Chia-I Lin, Yi-Wei Chiu, Meng-Syuan Yen, Yu-Wen Wang, Ying-Hsuan Wu, Ya-Hui Chuang.

   BACKGROUND: The liver's inherently immunosuppressive microenvironment presents a major barrier to effective immunotherapy for hepatocellular carcinoma (HCC). Although interleukin-10 (IL-10) has demonstrated antitumor activity in several cancer models, its therapeutic potential in HCC remains unclear. Here, we investigated whether liver-directed delivery of IL-10 using an adeno-associated virus vector (AAV-IL-10) could enhance antitumor immunity in HCC.
METHODS: Syngeneic orthotopic and intrahepatic metastatic HCC mouse models were used to evaluate the effects of liver-directed AAV-IL-10 therapy. Tumor burden, immune cell infiltration, and functional activation were assessed by flow cytometry and related analyses.
RESULTS: Liver-directed AAV-IL-10 treatment significantly reduced intrahepatic tumor burden and promoted robust infiltration of CD8+ T cells into the tumor microenvironment. AAV-IL-10 enhanced the functional activation of natural killer cells and CD8+ T cells, as reflected by increased expression of effector cytokines and cytotoxic molecules. Notably, AAV-IL-10 augmented the effector capacity of terminally exhausted CD8+ tumor-infiltrating lymphocytes and expanded a population of CD8+ T cells with a tissue-resident memory (Trm)-like phenotype. These Trm-like CD8+ T cells were liver-resident and persisted after tumor clearance. Importantly, the antitumor effects of AAV-IL-10 were confined to the liver and did not affect the growth of distant subcutaneous tumors.
CONCLUSIONS: Liver-directed AAV-IL-10 delivery overcomes local immunosuppression and enhances CD8+ T cell-mediated antitumor immunity in murine HCC models. These findings support targeted IL-10 delivery as a promising strategy to improve immunotherapy outcomes in liver cancer.

Keywords:  Cytokine; Gene therapy; Hepatocellular Carcinoma; Immunotherapy; T cell

DOI:  https://doi.org/10.1136/jitc-2025-012460
Cancer Commun (Lond). 2026 ;46 0021

TOPK Suppresses the CD8+ T Cell Antitumor Immunity via Modulation of IRF5 Expression.

Nianke Zang, Jinfeng Gan, Ye Chen, Zheng Huang, Chichu Xie, Junlong Dang, Changyuan Huang, Linjie Yang, Xuelian Chen, Guangli Rong, Jianbo Sun, Yiming Shao, Julie Wang, Guangying Qi, Yu Liu, Song Guo Zheng.

Background: T-LAK cell-originated protein kinase (TOPK), a serine/threonine kinase, is aberrantly overexpressed in human tumors and promotes malignant proliferation. Melanoma is a highly immunogenic tumor in which CD8+ T cell-mediated cytotoxicity is usually less effective in tumor control and responsive to immune checkpoint blockade. It is unclear whether the expression and functional characterization of TOPK within the immune cells affect the tumor microenvironment (TME) in patients with melanoma. This study aims to elucidate the expression pattern and immunoregulatory function of TOPK in CD8+ T lymphocytes during antitumor responses. Methods: Public single-cell RNA-sequencing (scRNA-seq) dataset analysis and flow cytometry assessed TOPK in tumor-infiltrating CD8+ T cells from patients with melanoma. Genetic deletion and pharmacological inhibition of TOPK using HI-TOPK-032 tested T cell-mediated melanoma control. Flow cytometry and tumor cell coculture killing assays measured effector release and target-cell apoptosis. Mechanistic analyses included assessment of interferon regulatory factor 5 (IRF5) expression, together with combination therapy using a programmed cell death protein 1 (PD-1)-blocking antibody in vivo. scRNA-seq of tumor-infiltrating lymphocytes (TILs) from Topk fl/fl and Cd8 Cre Topk fl/fl mice was also performed to define TOPK-dependent immune programs within the melanoma TME. Results: Single-cell transcriptomes identified a TOPK+ subset of tumor-infiltrating CD8+ T cells in melanoma, which was higher than that in normal lymph nodes (LNs), and exhibited suppressed cytotoxic and cytokine programs. CD8+ T cell-specific Topk deletion increased granzyme B (GzmB), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) secretion and improved tumor control. TOPK-deficient CD8+ T cells showed elevated activation-associated signaling pathways and immune effector gene expression. In murine TIL scRNA-seq, Cd8 Cre Topk fl/fl tumors exhibited increased effector and activation programs, reduced exhaustion and dysfunction programs, and enhanced immune crosstalk in the TME. Mechanistically, TOPK suppressed IRF5 expression and HI-TOPK-032 restored CD8+ T cell cytotoxicity in vitro and, with anti-PD-1, further inhibited tumor growth and increased intratumoral cytokine production. In human CD8+ T cells, enforced TOPK expression impaired cytotoxicity and cytokine secretion, reversed by IRF5 coexpression. Conclusions: These findings establish TOPK as the immune checkpoint limiting CD8+ T cell functionality in tumors and indicate the potential of TOPK inhibition as a strategy to augment T cell-based immunotherapies.

DOI: https://doi.org/10.34133/cancomm.0021
J Clin Lab Anal. 2026 Mar 24. e70196

Multi-Omics Profiling Uncovers Predictive Factors for Tumor-Infiltrating Lymphocyte Therapy in Ovarian Cancer.

Xiuzhen Wang, Rui Hou, Jinguo Chen, Bo He, Peiwen Liu, Genhai Zhu, Lan Hong, Wenjun Zhu.

BACKGROUND: Ovarian cancer (OC) remains a challenging malignancy with a poor prognosis, particularly in advanced stages. Tumor-infiltrating lymphocyte (TIL) therapy shows promise but has yielded inconsistent results in OC patients. This study aimed to identify factors predicting successful TIL isolation and expansion in OC.
METHODS: We performed multi-omics profiling on tumor samples from 10 OC patients, including whole-exome sequencing, bulk RNA sequencing, and single-cell RNA sequencing.
RESULTS: Genomic analysis revealed heterogeneity in tumor mutation burden, copy number variations, and homologous recombination deficiency status across patients. Single-cell profiling uncovered distinct cellular compositions in tumors, yielding successful TIL products (TIL+) vs. those that did not (TIL-). TIL+ tumors exhibited higher immune cell infiltration, particularly CD8+ effector and effector memory T cells. Metabolic profiling revealed enhanced activity in critical T cell subtypes within TIL+ tumors. Analysis of myeloid cells and fibroblasts identified subpopulations uniquely associated with TIL+ or TIL- samples. Cell-to-cell communication network analysis highlighted potential prognostic markers and interactions influencing TIL isolation outcomes.
CONCLUSION: Our findings provide insights into factors affecting TIL therapy efficacy in OC and suggest potential strategies for optimizing patient selection and TIL manufacturing protocols.

DOI: https://doi.org/10.1002/jcla.70196
Acta Otolaryngol. 2026 Mar 26. 1-7

Exploratory analysis of stromal and peritumoural tumour-infiltrating lymphocytes (tils) in malignant parotid gland tumours: associations with clinicopathological factors and survival.

Selçuk Erol, Ayça Arslan, Nazan Bozdoğan, I Emre Kiliç.

   BACKGROUND: The tumour immune microenvironment may influence prognosis in many cancers, but its significance in malignant parotid gland tumours is not well defined.
AIMS/OBJECTIVES: To evaluate whether stromal and peritumoural tumour-infiltrating lymphocyte (TIL) density is associated with clinicopathological features and overall survival in malignant parotid gland tumours.
MATERIAL AND METHODS: Thirty patients who underwent surgery for malignant parotid gland tumours (2013-2024) were retrospectively analysed. Stromal and peritumoural TIL densities were assessed on haematoxylin-eosin-stained sections and recorded as percentages. For exploratory survival analysis, TIL density was grouped as low-intermediate (0-40%) or high (50-90%). Overall survival was evaluated using Kaplan-Meier analysis and the log-rank test.
RESULTS: Mean age was 54.9 ± 16.1 years. Higher peritumoural TIL density was associated with longer overall survival (log-rank p = 0.045). No significant relationships were found between TIL density and other clinicopathological variables.
CONCLUSIONS AND SIGNIFICANCE: These exploratory findings suggest that increased peritumoural TIL density may indicate better survival in malignant parotid gland tumours. TIL assessment could provide prognostic information, but larger prospective studies are needed.

Keywords:  Parotid gland neoplasms; prognosis; survival; tumour-infiltrating lymphocytes

DOI:  https://doi.org/10.1080/00016489.2026.2646285
Ann Surg Oncol. 2026 Mar 21.

Salvage Metastasectomy After Adoptive Cell Transfer for Melanoma: Long-Term Updates.

Aaron J Dinerman, Alexandra M Gustafson, Kyle J Hitscherich, Donald E White, Sri Krishna, David S Schrump, Chuong D Hoang, Jonathan M Hernandez, Jared J Gartner, Paul F Robbins, Mei Li Kwong, Stephanie L Goff, James C Yang, Steven A Rosenberg, Nicholas D Klemen.

BACKGROUND: Adoptive cell transfer (ACT) can mediate durable regression in patients with metastatic melanoma, and some patients with initial response may progress, requiring salvage therapy.
METHODS: We report updated follow-up on a retrospective review of patients with metastatic melanoma receiving ACT at a single institution from 2000 to 2022. We identified patients with objective response (RECIST 1.0) or stable disease for at least 6 months (SD6) before experiencing oligoprogression in up to three extracranial sites managed with surgery. The primary outcomes were progression-free survival (PFS) and overall survival (OS) after surgery. We also performed an exploratory analysis for genomic mechanisms of tumor escape.
RESULTS: In total, 138 patients with metastatic melanoma treated with ACT had an objective response or SD6 before experiencing disease progression. Of these, 30 (21%) had extracranial oligoprogression managed with metastasectomy. With a median follow-up of 132 months (range 5-248), median OS was not reached and median PFS was 10.5 months. Ten-year OS was 54.7% and plateaued after 6 years. Four patients with pre- and post-ACT tumor sequencing demonstrated significant mutational evolution, with one patient experiencing loss of two major histocompatibility complex class I-restricted neoantigens recognized by T cells in the original infusion product.
CONCLUSIONS: Of patients experiencing oligoprogression after initial response to ACT (complete response, partial response, or SD6), 27% derived durable disease control after surgical management, confirming a potentially viable salvage option for "local" failures following ACT that may not portend systemic failure. Additional factors related to ACT response and oligoprogression that may guide patient selection for salvage metastasectomy remain undefined.

DOI: https://doi.org/10.1245/s10434-026-19354-1
Nat Immunol. 2026 Mar 27.

ZFP148 is a transcriptional repressor of cytolytic effector CD8+ T cell differentiation.

Tong Xiao, Xingyu Chen, No-Joon Song, Ryan J Brown, Anjun Ma, Jay K Mandula, Amir Yousif, Yi Wang, Minh Quynh May Le, Jianying Li, Fengxia Gao, Bella Weaver, Heng-Yi Chen, Fang-Yun Lay, Debasish Sundi, Maria Velegraki, Payton Weltge, Juanita L Merchant, Mark P Rubinstein, Kenneth J Oestreich, Chan-Wang Jerry Lio, Hazem E Ghoneim, Xue Li, Dan Theodorescu, Gang Xin, Qin Ma, Weiguo Cui, Zihai Li.

Progenitor CD8+ T cells differentiate into effector and exhausted progenies during chronic antigen stimulation; however, mechanisms that restrain exhaustion and sustain effector differentiation remain incompletely defined. Here we identified the transcription factor ZFP148 as a repressor of CD8+ T cell effector differentiation. ZFP148-deficient CD8+ T cells displayed increased frequency of cytolytic effector cells and reduced frequency of exhausted cells compared with Zfp148fl/fl controls during chronic viral infection. Mechanistically, ZFP148 limited the chromatin accessibility of effector-driving transcription factor motifs and directly repressed expression of the transcription factor KLF2. Furthermore, conditional ZFP148 ablation in CD8+ T cells synergized with programmed cell death-1 blockade to improve tumor control in syngeneic mouse models. Consistently, cancer patients with lower ZNF148 expression in tumor-infiltrating CD8+ T cells showed improved responsiveness to immunotherapies. Collectively, our study identifies ZFP148 as a transcriptional repressor of CD8+ T cell effector differentiation and highlights its therapeutic potential for enhancing antitumor immunity.

DOI: https://doi.org/10.1038/s41590-026-02461-2
Int J Mol Sci. 2026 Mar 10. pii: 2528. [Epub ahead of print]27(6):

Invariant Natural Killer T Cells in Cancer Immunotherapy: Lipid-Based Modulation, Nanotechnology, and Translational Advances.

Abdulaziz A Aloliqi, Abdullah M Alnuqaydan, Mohammad Alshebremi, Arif Khan, Masood Alam Khan.

  Invariant natural killer T (iNKT) cells are a unique lymphocyte subset that bridge innate and adaptive immunity through recognition of glycolipid antigens presented by CD1d. Upon activation by ligands such as α-galactosylceramide (α-GalCer), iNKT cells rapidly secrete cytokines, including IFN-γ and TNF-α, thereby activating dendritic cells, natural killer (NK) cells, and cytotoxic T lymphocytes (CTLs) to promote antitumor immunity. Despite their therapeutic promise, clinical translation has been limited by rapid α-GalCer clearance, induction of iNKT cell anergy following repeated stimulation, and the immunosuppressive tumor microenvironment (TME). Recent advances in lipid-engineered nanoparticle systems offer solutions to these challenges by improving ligand stability, enhancing antigen-presenting cell targeting, and enabling controlled release that sustains Th1-biased activation while reducing anergy. Liposomal and polymer-based nano-formulations enhance bioavailability and promote more durable IFN-γ-mediated responses. In parallel, chimeric antigen receptor (CAR)-engineered iNKT cells provide antigen-specific tumor targeting while preserving intrinsic CD1d-restricted immunomodulatory functions, demonstrating encouraging safety and efficacy in early-phase studies. Combination strategies further strengthen iNKT-based immunotherapy. Integration with chemotherapy, immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4, and cytokine support enhances effector activation, counteracts TME-induced suppression, and improves therapeutic outcomes. However, challenges remain, including optimization of dosing, control of off-target immune activation, scalable manufacturing, and long-term safety evaluation. Collectively, the convergence of nanotechnology, CAR engineering, and rational combination approaches establishes iNKT cell-based therapy as a promising next-generation immunotherapeutic strategy. Continued refinement of delivery systems, genetic engineering platforms, and translational protocols may enable durable immune reprogramming and improved clinical outcomes in resistant and immunosuppressive cancers.

Keywords:  cancer immunotherapy; iNKT cells; nanoparticles; tumor microenvironment; α-GalCer

DOI:  https://doi.org/10.3390/ijms27062528
Cells. 2026 Mar 10. pii: 494. [Epub ahead of print]15(6):

Re-Tooling of γδ T Cells for Cancer Immunotherapy Using Advanced Manufacturing and Genetic Engineering.

Benjamin J L Lim, John Maher.

  Adoptive immunotherapy using ex-vivo-amplified autologous αβ T cells has achieved notable success in the treatment of diverse cancer types. Pre-eminent among these developments has been the advent of chimeric antigen receptor (CAR) T cell therapy, which has revolutionised the treatment of selected haematological malignancies. However, autologous CAR T cell immunotherapy is poorly scalable and has demonstrated limited efficacy against solid tumours. Accordingly, there has been significant interest in alternative strategies that may bridge these gaps. The use of γδ T cells is an attractive alternative since they possess intrinsic anti-tumour activity and do not elicit graft versus host disease (GvHD) when employed as an allogeneic drug product. In this review, we evaluate the potential use of γδ T cells for cancer immunotherapy and how manufacturing and genetic engineering refinements can be used to potentiate this activity. We also summarise current clinical experience with CAR γδ T cell therapies and discuss the implications of these findings for the next generation of cellular immunotherapies.

Keywords:  chimeric antigen receptor; immunotherapy; malignancy; γδ T cell

DOI:  https://doi.org/10.3390/cells15060494
Biomed Pharmacother. 2026 Mar 20. pii: S0753-3322(26)00280-5. [Epub ahead of print]198 119247

Advancing adoptive cellular immunotherapy via Notch-based ex vivo T cell development platforms.

Andrea Z Tuckett, Johannes L Zakrzewski.

  T cell-based immunotherapies represent one of the most promising areas in cancer treatment, offering the dual advantages of precise molecular targeting and durable therapeutic effects. Notch signaling platforms facilitate the ex vivo generation of T lineage cells from hematopoietic stem and progenitor cells sourced from bone marrow, peripheral blood, cord blood, or pluripotent stem cells. These platforms can be tailored to produce either T cell progenitors or fully differentiated T cells. The use of T cell precursors in adoptive cell therapy enables off-the-shelf immunotherapy, as even fully HLA-mismatched allogeneic T cell precursors undergo thymic selection and are tolerized during maturation in the recipient's thymus. Furthermore, T lineage cells produced via Notch-based systems can be engineered to express chimeric antigen receptors, resulting in potent, tumor-specific therapeutic products. Notch-based in vitro T cell development platforms range from stromal cell-dependent co-cultures to clinically suitable, stromal cell-free systems using immobilized Notch ligands, ligand-coated microbeads or soluble Notch agonists. Enhancements such as incorporating VCAM-1 alongside Notch signaling have been introduced to improve the efficiency of T cell production. This review highlights the various Notch signaling platforms that have contributed - and continue to contribute - to the advancement of adoptive T cell immunotherapy.

Keywords:  Adoptive cellular therapy; Notch signaling; Off-the-shelf; T cell development

DOI:  https://doi.org/10.1016/j.biopha.2026.119247
J Hepatocell Carcinoma. 2026 ;13 575861

Integrative Single-Cell and Spatial Transcriptomic Analysis Reveals MAIT Cell Dysfunction in Relapsed HCC.

Geon Woo Park, Hayoung Jang, Thuy Nguyen-Phuong, Hyunsung Nam, Chung-Gyu Park, Gwang Hyeon Choi, Sook-Hyang Jeong, Jin-Wook Kim, Chang Jin Yoon, Jae Hwan Lee, Hyun Je Kim.

   Purpose: Hepatocellular carcinoma (HCC) frequently recurs after curative treatment, and the tumor immune microenvironment plays an important role in disease progression. However, the role of mucosal-associated invariant T (MAIT) cells in relapsed HCC remains poorly understood. This study aimed to characterize transcriptional and spatial features of MAIT cells in relapsed HCC and their association with malignant hepatocyte phenotypes.
Patients and Methods: Tumor samples from primary (n = 3) and relapsed (n = 2) HCC patients were analyzed using paired single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics. scRNA-seq data (49,229 cells) were processed using Seurat with standard quality-control thresholds, followed by Harmony batch correction and unsupervised clustering. Malignant hepatocytes were identified by copy-number variation inference. Spatial transcriptomic data from 35 regions of interest were normalized and deconvolved using scRNA-seq-derived reference profiles. Independent validation was performed using a public HCC scRNA-seq dataset.1.
Results: Integrated analyses revealed distinct tumor microenvironmental features in relapsed HCC. Relapsed tumors showed increased representation of malignant hepatocytes with elevated cancer stemness-related transcriptional signatures compared with primary tumors (1.18-fold increase, p < 0.0001), which was spatially supported by enrichment in tumor regions (1.10-fold increase, p ≤ 0.05). Within the T/NK compartment, MAIT cells were significantly enriched in relapsed tumor regions (2.71-fold increase, p ≤ 0.05). Transcriptomic profiling identified distinct MAIT cell states between primary and relapsed HCC, with relapsed MAIT cells displaying dysfunctional phenotype. Cell-cell interaction analysis suggested enhanced ligand-receptor interactions between MAIT cells and malignant hepatocytes in relapsed tumors. In the TCGA LIHC cohort, high relapsed MAIT cell signature scores were associated with poorer overall survival (HR = 1.52, p ≤ 0.05).
Conclusion: Relapsed HCC is characterized by enhanced malignant hepatocyte stemness and altered MAIT cell states within the tumor microenvironment. These findings suggest an association between MAIT cell dysregulation and relapse-specific tumor biology, warranting further functional investigation.

Keywords:  hepatocellular carcinoma; mucosal-associated invariant t cells; tumor microenvironment; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.2147/JHC.S575861
Front Med (Lausanne). 2026 ;13 1792692

Integration of dual-energy CT parameters and radiomics features for non-invasive prediction of α-SMA and CD8 + T cell in non-small cell lung cancer.

Nan Jiang, Yan Zhang, Gang-Feng Li, Xiao-Yan Qu, Wen-Xiu Wang, Rong Hou, Hong-Juan Ma, Yang Yang, Ying Yu, Guang-Bin Cui.

   Background: The non-invasive characterization of the tumor microenvironment (TME) is essential for stratifying non-small cell lung cancer (NSCLC) patients who may benefit from immunotherapy. This study investigates a novel approach by integrating dual-energy CT (DECT) parameters with radiomics to quantitatively assess stromal fibrosis (via α-SMA area) and CD8 + T-cell infiltration.
Methods: In this prospective study, 70 treatment-naive NSCLC patients were enrolled. Preoperative DECT scans were used to extract both DECT parameters and radiomics features. Corresponding surgical specimens were analyzed to determine the area percentage of α-SMA-positive stroma and the density of CD8 + T cells, with patients classified into high and low groups for each biomarker. After feature selection, models were constructed based on DECT parameters alone, radiomics features alone, and a combined feature set. Models were evaluated via 5-fold cross-validation.
Results: For predicting high α-SMA expression, the integrated model combining DECT parameters and radiomics features demonstrated superior performance (AUC: 0.766) compared to models using either modality alone (DECT AUC: 0.670; radiomics AUC: 0.703). In contrast, for predicting CD8 + T-cell density, the DECT-only model (AUC: 0.715) performed comparably to the radiomics model (AUC: 0.695), with no significant gain from integration. Key discriminating features, such as normalized iodine concentration for α-SMA and spectral slope of K40-70 for CD8+, showed significant intergroup differences and plausible biological correlations.
Conclusion: The integration of DECT and radiomics presents a feasible, non-invasive strategy to assess specific TME components in NSCLC, underscoring the complementary value of different imaging data types towards developing biomarkers for personalized oncology.

Keywords:  CD8 + T lymphocyte; dual energy CT; non-small cell lung cancer; radiomics; tumor microenvironment; α-SMA

DOI:  https://doi.org/10.3389/fmed.2026.1792692