bims-tuinly Biomed News
on Tumor-infiltrating lymphocytes therapy
Issue of 2026–02–08
twenty-six papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Harnessing Tumor-Infiltrating Lymphocytes for Improved Cancer Outcomes.
  2. Patient-derived models of tumor-immune cell interactions.
  3. Refining Stage II Melanoma Risk Stratification Through Tumor-Infiltrating Lymphocyte Assessment.
  4. TILseg: Automated Whole Slide-Level Spatial Scoring of Tumor-Infiltrating Lymphocytes Reveals Prognostic Patterns in Triple Negative Breast Cancer.
  5. NEO-STIM advances personalized neoantigen-specific adoptive T cell therapy.
  6. Aldehyde and seek: Toxic aldehydes drive exhaustion in tumor-infiltrating T cells.
  7. Metabolism of tumor infiltrating T cells.
  8. Cancer immunotherapy insights: key takeaways from the ADSCC bone marrow and cellular therapy congress 2024.
  9. Automated quantification of tumor-infiltrating lymphocytes by machine learning reveals prognostic and immunogenomic features in lung cancer.
  10. The evolution of cellular-based immunotherapy in the treatment of gastric cancer: an overview of clinical trials.
  11. Organoid-Immune Co-Cultures: A Next-Generation approach to disease modeling.
  12. Evaluation of histomorphological changes in breast cancer following neoadjuvant therapy at a tertiary care centre, Jharkhand.
  13. Making sense of TILs: recommendations for morphological assessment of tumour-infiltrating lymphocytes in gastro-oesophageal carcinoma: A report on behalf of the International Immuno-Oncology Biomarker Working Group.
  14. Tenascin-XB plays a role in the infiltration of immune cells in tumor microenvironment.
  15. Generation and functional evaluation of STAb-T cells.
  16. Stochasticity in cancer immunotherapy stems from rare but functionally critical Spark T cells.
  17. Systems mapping of intra-donor, cross-tissue T cell clonal expansion and tissue adaptation in the gut-liver-blood axis.
  18. Zbtb32 promotes CD8+ T cell differentiation and function in cancer.
  19. Dysregulated expression of the tumor suppressor p14ARF in cancer provides an effective target for TCR-T cell therapeutics.
  20. CD8/CD4 ratio, CD56, and PD-L1 as prognostic markers in sinonasal mucosal melanoma.
  21. NR4A1 limits CD8 + T Cell effector responses and protection in tuberculosis.
  22. Macrophage-derived chemokines in T cell regulation: implications for cancer immunotherapy.
  23. Atlas-guided discovery of transcription factors for T cell programming.
  24. Ibrutinib enhances stem-cell-memory T cell generation during early T cell activation but inhibits T cell proliferation.
  25. Autophagy-driven CCL7+ monocyte terminal differentiation program fuels CD8+ T cell-mediated cardiac injury in Sepsis.
  26. Clinical characteristics and survival outcomes of young women with luminal HER2-low and HER2-ultralow breast cancer.
  1. Iran J Pathol. 2026 ;21(1): 143-145
    Harnessing Tumor-Infiltrating Lymphocytes for Improved Cancer Outcomes.
    Gunvanti Rathod, Pragnesh Parmar.
      
    DOI:  https://doi.org/10.30699/ijp.2025.2068603.3502
  2. Methods Cell Biol. 2026 ;pii: S0091-679X(25)00201-8. [Epub ahead of print]201 195-218
    Patient-derived models of tumor-immune cell interactions.
    Niloofar Nemati, Nina Boeck, Zlatko Trajanoski.
      Novel therapeutic approaches highlight the need for advanced ex vivo cell culture models that more closely resemble the physiological and genetic properties of the primary tumor. Patient-derived models could serve as an attractive strategy to investigate the crosstalk between cancer cells and its microenvironment and to test potential therapeutic targets, paving the way for precision oncology. In this chapter, we provide a detailed step-by-step protocol for enabling a direct co-culture system of patient-derived colorectal cancer (CRC) organoids with autologous tumor-infiltrating lymphocytes (TILs). The present protocol provides a methodology to gain direct access to the apical side of the epithelial cells forming the organoids. This method can be used to investigate patient-specific cell-to-cell interactions, T cell functionality and efficacy and provides a robust platform to validate potential immunogenic neoantigens.
    Keywords:  Co-culture; Ex vivo cell culture models; Immunotherapy; Organoids; Precision oncology; Tumor-immune cell interactions; Tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1016/bs.mcb.2025.10.001
  3. J Am Acad Dermatol. 2026 Feb 04. pii: S0190-9622(26)00131-3. [Epub ahead of print]
    Refining Stage II Melanoma Risk Stratification Through Tumor-Infiltrating Lymphocyte Assessment.
    Zunjiang Zhao, Kai Peng, Yeqin Shen.
      
    Keywords:  Melanoma; Prognostic Accuracy; Tumor-Infiltrating Lymphocytes
    DOI:  https://doi.org/10.1016/j.jaad.2025.12.115
  4. medRxiv. 2026 Jan 21. pii: 2026.01.08.26343727. [Epub ahead of print]
    TILseg: Automated Whole Slide-Level Spatial Scoring of Tumor-Infiltrating Lymphocytes Reveals Prognostic Patterns in Triple Negative Breast Cancer.
    Lisa L Carr, Abishek Sankaranarayanan, Khanh Ha, Meenal Rawlani, Anum S Kazerouni, Jennifer Specht, Laura C Kennedy, Daniel Reiter, Suzanne Dintzis, Daniel S Hippe, Mark R Kilgore, Lynn Symonds, Savannah C Partridge, Shachi Mittal.
      Stromal tumor-infiltrating lymphocytes (sTILs) are promising biomarkers for predicting therapeutic outcomes in triple-negative breast cancer (TNBC), with higher sTIL levels correlating with improved chemotherapy response and survival outcomes. Currently, sTILs are manually evaluated by pathologists, which is prone to inter-reader variability. In this study, we have developed an AI-driven TIL segmentation pipeline to process entire diagnostic hematoxylin-and-eosin-stained whole slide images for reproducible scoring (global TILseg scoring) and reliable prognostication. This pipeline was optimized and tested using two independent TNBC patient cohorts (n = 57 in the discovery cohort, n = 43 in the validation cohort) with clinical outcomes and follow-up data. The global scores generated by TILseg showed moderate to high concordance with expert scoring (Spearman R = 0.84-0.89) and improved patient stratification (p-value = 0.0191) as compared to manual scoring (p-value = 0.0663). Additionally, we investigate how the spatial localization of sTILs (spatial TILseg) impact survival outcomes by identifying TILs in selected stromal subsets (0.02-2 mm from the epithelial clusters). Our findings have shown that TILs up to 50 µm from epithelial regions prove to be most prognostic in predicting recurrence-free survival post-neoadjuvant chemotherapy with higher statistical significance than both manual and global TILseg scoring. Further, spatial TILseg scoring was more significantly associated with pathological complete response status in both patient cohorts. In summary, we present an AI-based digital tool for robust sTIL scoring and spatial mapping to enhance its potential as both a diagnostic and prognostic biomarker, particularly in TNBC patients.
    SIGNIFICANCE: An automated and spatially resolved AI tool for sTILs scoring enhances patient risk stratification based on both response to treatment and recurrence-free survival, establishing its relevance as an independent prognostic marker.
    DOI:  https://doi.org/10.64898/2026.01.08.26343727
  5. Nat Commun. 2026 Feb 05.
    NEO-STIM advances personalized neoantigen-specific adoptive T cell therapy.
    Divya Lenkala, Jessica Kohler, Brian McCarthy, Michael Nelson, Noor A M Bakker, Renate de Boer, Emily K Jackson, Joong Hyuk F Sheen, Susan Hannes, Ekaterina Esaulova, Kai Stewart, Claudia Gottstein, John Attanasio, Flavian D Brown, Sebastian Hymson, Shirisha Meda, Maaike van Zon, Saskia Scheij, Rhianne Voogd, Brenda Raud, Ziyan Xu, Jessica S W Borgers, Maartje W Rohaan, Kristen N Balogh, Asaf Poran, Michael Rooney, Jesse Z Dong, John R Srouji, Vikram R Juneja, Christina M Arieta, Cynthia M Nijenhuis, Bastiaan Nuijen, Mark DeMario, Kelledy Manson, Ton N M Schumacher, Richard B Gaynor, John B Haanen, Joost H van den Berg, Marit M van Buuren.
      Neoantigen-based adoptive T cell therapies (ACTs) represent a promising avenue in cancer immunotherapy due to their exquisite tumor specificity. The first cell-based immunotherapy for a solid tumor, comprising tumor-infiltrating lymphocytes, recently received FDA approval. Building on this, we designed a distinct ACT approach, where T cell responses against personalized neoantigens are systematically generated from autologous peripheral blood. Here we report the establishment of NEO-STIM, an ex vivo induction process to prime and expand pre-existing memory and de novo CD8+ and CD4+ T cell responses, thereby highlighting critical parameters for generating potent neoantigen-specific T cell responses. The drug products comprise mutant-reactive, polyfunctional, and cytotoxic CD8+ and CD4+ T cells, able to recognize autologous tumor material. Following infusion, T cell responses are detected in tumor and blood of a patient, and display activated/exhausted and cytotoxic phenotypes. A first-in-human clinical trial (NCT04625205) recently further validated proof-of-concept, supporting continued development of this ACT approach.
    DOI:  https://doi.org/10.1038/s41467-026-68680-1
  6. Sci Immunol. 2026 Feb 06. 11(116): eaef9196
    Aldehyde and seek: Toxic aldehydes drive exhaustion in tumor-infiltrating T cells.
    Cait A McAlindon, Rachael A Clark.
      Aldehydes accumulating in response to reduced fatty acid oxidation in tumor-infiltrating lymphocytes damage mitochondria and drive T cell exhaustion.
    DOI:  https://doi.org/10.1126/sciimmunol.aef9196
  7. Front Immunol. 2025 ;16 1711328
    Metabolism of tumor infiltrating T cells.
    Hildegund Cj Ertl.
      The microenvironment of solid tumor is commonly low in key nutrients such as glucose providing metabolic challenges for tumor infiltrating T lymphocytes (TIL), which upon activation switch to glycolysis to meet their need for energy and effector molecule production. Consequently, TIL become functionally impaired and die unless they can switch their metabolism to alternative pathways such as oxidative phosphorylation catabolizing lipids that are in ample supply within solid tumors. Medicinal interventions that alter the nutrient supply within tumors or that facilitate the TIL's metabolic switch away from glycolysis have been tested in experimental animals and clinical trials. Some of them were shown to increase TIL functions, prolong their survival and enable them to slow tumor progression.
    Keywords:  T cells; cancer; glycolysis; metabolism; oxidative phosphorylation
    DOI:  https://doi.org/10.3389/fimmu.2025.1711328
  8. Front Immunol. 2025 ;16 1650023
    Cancer immunotherapy insights: key takeaways from the ADSCC bone marrow and cellular therapy congress 2024.
    Gisela Maria Suárez Formigo, Zaima Mazorra, Cinthia Olexen, Tamara Menéndez, Loubna Abdel Hadi, Rupert Handgretinger, Antonio Alfonso Bencomo Hernandez, Inas El Najjar, George Coukos, Helen Sabzevari, Catherine Bollard, Daniel Couriel, David Wald, Mohamad Hamieh, Javier Briones, Fatima Al Kaabi, Yendry Ventura-Carmenate.
      The rising global cancer burden underscores the urgent need for innovative and effective therapies. Molecular and cellular immunology advances have revolutionized cancer immunotherapy, transforming laboratory discoveries into clinical breakthroughs. The Second Bone Marrow Transplant and Cellular Therapy Congress, held in Abu Dhabi, United Arab Emirates (UAE), on October 26th - 27th, 2024, and sponsored by the Abu Dhabi Stem Cells Center (ADSCC), convened global experts to discuss cutting-edge developments in adoptive cell transfer (ACT); chimeric antigen receptor T-cell (CAR-T) therapy, tumor-infiltrating lymphocyte (TIL) engineering and T-cell receptor (TCR) innovations. Discussions covered key challenges such as tumor microenvironment (TME) resistance, antigen escape, manufacturing complexity, cost-effectiveness, and accessibility. Experts emphasized the crucial role of biomarker identification in optimizing patient selection and improving treatment efficacy. Additionally, emerging strategies were highlighted to enhance the durability and specificity of cellular therapies, including next-generation CAR-T designs, combination approaches, and novel gene-editing technologies. With over 2,300 participants from academia, research, and healthcare, the event fostered international collaborations and knowledge exchange. The ADSCC continues to play a pivotal role in integrating advanced cellular therapies into healthcare systems, contributing to the expansion of precision oncology in the UAE and beyond. This review analyzes the latest advances in immunotherapy, highlighting their clinical impact, challenges, and future directions in the evolving landscape of cancer treatment, as debated during the congress.
    Keywords:  CAR-T cells; Tumor microenvironment (TME); Tumor-infiltrating Lymphocytes (TILs); adoptive cell transfer; cancer immunotherapy; precision medicine
    DOI:  https://doi.org/10.3389/fimmu.2025.1650023
  9. Sci Rep. 2026 Feb 02.
    Automated quantification of tumor-infiltrating lymphocytes by machine learning reveals prognostic and immunogenomic features in lung cancer.
    Ang Li, Yutao Pang, Hongfei Zhang, Dong Wu, Liyao Lin, Zhan He, Zhu Liang, Jie Chen, Fasheng Li.
      
    Keywords:  Digital pathology; Immune microenvironment; Lung adenocarcinoma; Machine learning; Tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1038/s41598-026-37076-y
  10. Clin Transl Oncol. 2026 Feb 03.
    The evolution of cellular-based immunotherapy in the treatment of gastric cancer: an overview of clinical trials.
    Lang Wu, Jasur Rizaev, Khaled Fahmi Fawy, Mustafa Jawad Kadham, Nabieva Dildora, Shakhlokhon Kurbanova, Zamira Atamuratova, Asilbek Dauletbaev, Natrayan Lakshmaiya, Raed Fanoukh Aboqader Al-Aouadi.
      Despite advances in patients' healthcare, gastric cancer remains a major health concern around the world with a high annual incidence rate and mortality. This highlights the urgent need to develop more effective therapeutic strategies, particularly for patients in advanced stages of the disease. In the recent decade, cellular-based immunotherapy has achieved remarkable successes in various hematologic malignancies and solid tumors. Nonetheless, until now, no cellular-based immunotherapy has been approved for GC patients. This review aims to provide a holistic view of the current state of cellular-based immunotherapy for GC, its existing bottlenecks, and future directions to harness the potential of cellular-based immunotherapy for GC treatment. In this regard, we explore clinical trials of various types of cellular-based immunotherapy, including chimeric antigen receptor (CAR)-engineered cell therapy, T cell receptor (TCR)-engineered T cell therapy, tumor-infiltrating lymphocyte (TIL) therapy, cytokine-induced killer (CIK) cell therapy, and dendritic cell (DC) vaccines. For each type of cellular-based immunotherapy, we discuss existing roadblocks to successful treatment and explore potential solutions that may improve efficacy, including novel targets, combination approaches, and biomarker-driven patient selection.
    Keywords:  Cellular-based immunotherapy; Clinical trials; Gastric cancer; Immunotherapy; Stomach cancer
    DOI:  https://doi.org/10.1007/s12094-025-04175-7
  11. Mol Biol Rep. 2026 Feb 04. 53(1): 360
    Organoid-Immune Co-Cultures: A Next-Generation approach to disease modeling.
    Fatemeh Najafi, Negin Alidoost Zoghi, Hanie Khalili, Niki Najafi, Mohammad Hosein Yazdi, Mahsa Mollapour Sisakht.
      The incorporation of organoids with immune cells in co-culture systems signifies a groundbreaking advancement in the fields of cancer research and immunology. These three-dimensional models, derived from primary tumor specimens or stem cells, provide a more accurate representation of the tumor microenvironment (TME) than conventional two-dimensional cultures or animal models. This enhanced model allows for a thorough examination of the intricate interactions between cancer cells and the immune system. Although the success rates for organoid initiation can vary, averaging 36.8% across 13 different tumor types, successful organoid establishment enables the co-culture with a variety of immune cells, such as T cells, tumor-infiltrating lymphocytes (TILs), peripheral blood mononuclear cells (PBMCs), macrophages, dendritic cells, and natural killer (NK) cells. This platform enables the study of immune responses to cancer, mechanisms of immune evasion, and the influence of the TME on immune activation and suppression. The review emphasizes research involving intestinal, pancreatic, brain, liver, and cervical organoids, highlighting their role in elucidating disease mechanisms, assessing the effectiveness of immunotherapies (including checkpoint inhibitors and therapeutic vaccines), and conducting preclinical drug evaluations. Notable examples include modeling graft-versus-host disease with intestinal organoids, investigating the influence of DCLK1 on immunosuppression in pancreatic cancer, evaluating the effectiveness of engineered T cells against neuroblastoma using brain organoids, and analyzing the effects of cancer-associated fibroblasts on drug responses in colon cancer. Additionally, the potential of organoids in vaccine development and testing, particularly for influenza and other viral infections, is examined, demonstrating their utility in assessing immune responses and vaccine effectiveness. Despite existing challenges, such as the relatively low efficiency of organoid generation and the complexities involved in fully mimicking the TME, ongoing technological innovations, including tumor-on-chip systems and enhanced matrix materials, are expected to improve the functionality and clinical applicability of these advanced in vitro models.
    Keywords:  Co-culture; Disease modeling; Immune cell; Organoid
    DOI:  https://doi.org/10.1007/s11033-026-11450-5
  12. Bioinformation. 2025 ;21(10): 3770-3774
    Evaluation of histomorphological changes in breast cancer following neoadjuvant therapy at a tertiary care centre, Jharkhand.
    Chanchal Ashok, Arvind Kumar, Aditi Priya, Saurav Banerjee, Alimuddin Ansari, Sunil Mahto.
      Breast cancer remains a major cause of cancer-related mortality among women worldwide, with treatment response prediction posing a persistent challenge. Neoadjuvant therapy (NAT) offers tumor downstaging and assessment of histopathological response. In this prospective study of 125 patients, NAT led to a significant reduction in tumor cellularity (82.4% ± 12.3% to 31.7% ± 18.9%, p < 0.001) and increased fibrosis (15.2% ± 8.7% to 48.6% ± 15.4%, p < 0.001). Pathological complete response (pCR) occurred in 32% of patients, with higher rates in triple-negative (42.1%) and HER2-positive (38.5%) subtypes. High post-NAT tumor-infiltrating lymphocytes correlated strongly with pCR (r = 0.67, p < 0.001). Thus, we show that NAT induces significant histomorphological changes, which can serve as key prognostic indicators for therapeutic response and patient outcomes.
    Keywords:  Breast cancer; changes; histological; therapy
    DOI:  https://doi.org/10.6026/973206300213770
  13. Histopathology. 2026 Feb 05.
    Making sense of TILs: recommendations for morphological assessment of tumour-infiltrating lymphocytes in gastro-oesophageal carcinoma: A report on behalf of the International Immuno-Oncology Biomarker Working Group.
    Ylva A Weeda, Roberto Salgado, Filip van Herpe, Daniel Sur, Michael Vieth, Sherene Loi, Ahmad P Tafti, Hardas Alexandros, Akira I Hida, Amarpreet Bhalla, Andrey I Khramtsov, Anna Ehinger, Atsushi Tanaka, Balazs Acs, Caner Ercan, Cornelia M Focke, Daniel Ehinger, Dan Huang, Galina F Khramtsova, Haruto Nishida, Nianyi Li, Nickolas Littlefield, Sanna Steen, Selim Sevim, Shin Ichihara, Shinnosuke Morikawa, Stefan Michiels, Thomas Papathomas, Toshihiro Haga, Qiangqiang Gu, Weiqi Sheng, Hoel Kervadec, Hugo M Horlings, Francisco Sanchez-Vega, Yelena Y Janjigian, Myriam Chalabi, Hanneke W M van Laarhoven, Liudmila L Kodach, Sybren L Meijer.
      In the era of immune checkpoint inhibitors for cancers, the need for prognostic biomarkers to identify patients most likely to achieve a durable response has become increasingly more relevant. Tumour-infiltrating lymphocytes (TILs) have gained significant interest, as they can be evaluated using standard haematoxylin and eosin-stained slides, making it a widely accessible and cost-effective biomarker. In addition to their practicality, TILs provide prognostic insights into the interplay between the immune system and tumour cells. While the morphological assessment of TILs has been standardised in breast cancer, comprehensive guidelines for their evaluation in gastro-oesophageal carcinomas (GEC) are still lacking. This narrative review examines the current literature on the composition, clinical implications and therapeutic utility of TILs in GEC. These insights are used to propose a framework with recommendations for standardised evaluation and reporting of TILs in GEC, while also highlighting pitfalls specific to GEC pathology. These recommendations serve as a vital first step towards the widespread use and validation of TILs as a biomarker.
    Keywords:  gastro‐oesophageal cancer; tumour‐infiltrating lymphocytes
    DOI:  https://doi.org/10.1111/his.70089
  14. Biomed Res. 2026 ;47(1): 11-23
    Tenascin-XB plays a role in the infiltration of immune cells in tumor microenvironment.
    Ao Gong, Yuichi Iida, Kohei Kawakami, Kazuo Yamada, Yasuyuki Saito, Ken-Ichi Matsumoto.
      We previously showed that tenascin-XB (TNXB) contributes to tumor suppressor function. The present study aimed to assess the tumor-suppressive mechanism of TNXB by focusing on immune cell infiltration into the tumor microenvironment (TME). We revealed that B16-OVA melanoma cells (MO5)-bearing TNXB-deficient (Tnxb-/-) mice exhibited significant tumor progression and a poor survival rate. Allogeneic mixed lymphocyte reaction showed reduced numbers and increased activation of both CD4+ and CD8+ T cells from Tnxb-/- spleens. Moreover, T cell activation assay further proved that CD4+ and CD8+ T cells from Tnxb-/- mice were more activated than those from WT mice. RT-qPCR analysis showed that expression of T cell activation-related cytokines and chemokines was significantly decreased in tumor tissues from Tnxb-/- mice. Flow cytometry analysis revealed a reduced infiltration level of CD8+ T cells in both naïve spleens and tumor tissues in Tnxb-/- mice. Ultimately, total activation of CD8+ T cells was decreased in tumor tissues in Tnxb-/- mice. In conclusion, we found that although Tnxb-/- CD4+ and CD8+ T cells tend to be activated more than WT CD4+ and CD8+ T cells, CD8+ T cell infiltration and activation level were attenuated in tumor sites of Tnxb-/- mice.
    Keywords:  Ehlers-Danlos syndrome; Extracellular matrix glycoprotein; T cell infiltration; tenascin-XB; tumor microenvironment; tumor-bearing mice
    DOI:  https://doi.org/10.2220/biomedres.47.11
  15. Methods Cell Biol. 2026 ;pii: S0091-679X(25)00091-3. [Epub ahead of print]201 1-22
    Generation and functional evaluation of STAb-T cells.
    Anaïs Jiménez-Reinoso, Belén Blanco, Luis Álvarez-Vallina.
      STAb-T therapy is an emerging cancer immunotherapy strategy that combines the advantages of adoptive cell therapies and bispecific antibodies. STAb (Secreting T cell engager bispecific Antibodies) T cells are T lymphocytes genetically engineered to secrete bispecific T cell engagers (TCEs) that recruit T cells to target and destroy tumor cells. Adoptive transfer of STAb-T cells has demonstrated potent anti-tumor activity in preclinical models and evaluation in human patients is forthcoming. Here, we provide comprehensive guidelines for generating STAb-T cells and assessing their functionality and efficacy in vitro and in relevant in vivo models of hematological malignancies.
    Keywords:  Cancer immunotherapy, adoptive T cell therapy, bispecific antibodies, T cell engagers, STAb-T cells
    DOI:  https://doi.org/10.1016/bs.mcb.2025.03.010
  16. Cell. 2026 Feb 05. pii: S0092-8674(25)01439-4. [Epub ahead of print]
    Stochasticity in cancer immunotherapy stems from rare but functionally critical Spark T cells.
    Emanuel Salazar-Cavazos, Dongya Jia, Yoann Missolo-Koussou, Adam L Kenet, Sooraj R Achar, Hannah Dada, Taisuke Kondo, Anagha Krishnan, Naomi Taylor, Nicholas D Klemen, Peng Jiang, Joshua J Waterfall, Don L DeVoe, Grégoire Altan-Bonnet.
      Cancer immunotherapies trigger highly variable responses in patients and in genetically identical mouse models. To assess the intrinsic stochasticity of these therapies, we performed thousands of well-controlled ex vivo immunoassays. We show that leukocyte responses and tumor cytotoxicity are highly variable at the macroscopic level and statistically distributed as a shifted Poisson process. Stochastic activation of a rare subpopulation of T cells (so-called Spark T cells), coupled with a paracrine interferon (IFN)-γ-driven positive feedback, accounts for this measured "noise" in immunotherapeutic reactions. We integrated these quantitative insights into a custom-designed machine-learning pipeline to analyze immune reactions with single-cell resolution. This led us to phenotypically and functionally identify Spark T cells in murine naive T cells and in human T cell blasts as prepared for adoptive T cell therapy. We then demonstrate their relevance in explaining variable outcomes in cancer immunotherapies.
    Keywords:  T cells; cancer; high throughput; immuno-oncology; immunotherapy; machine learning; stochasticity; theoretical modeling; tumor immunology; variability
    DOI:  https://doi.org/10.1016/j.cell.2025.12.026
  17. Cell Rep. 2026 Jan 29. pii: S2211-1247(25)01688-2. [Epub ahead of print]45(2): 116916
    Systems mapping of intra-donor, cross-tissue T cell clonal expansion and tissue adaptation in the gut-liver-blood axis.
    Ran Ran, Merve Uslu, Mohd Farhan Siddiqui, Douglas K Brubaker, Martin Trapecar.
      The human gut-liver axis is a critical immunological interface, yet factors that shape T cell adaptation and clonal expansion across tissues remain unclear. We performed integrated single-cell RNA and T cell receptor sequencing on T cells from matched colon epithelium, lamina propria, liver, and blood of the same donors, enabling clonal tracking and tissue-specific transcriptional profiling without inter-individual confounders. Colonic intraepithelial lymphocytes were largely clonally distinct from lamina propria T cells. Tissue-resident T cells in colon vs. liver displayed marked transcriptional divergence, with colonic lamina propria tissue-resident memory T cells (TRMs) enriched for interferon-stimulated genes (e.g., ISG15 and IFITM3). Ligand-receptor analysis implicated liver-derived factors, including fibrinogen gamma chain, in shaping colon TRM states. Across tissues, highly expanded clones of the same cell type shared a core upregulated gene set, suggesting common determinants of clonal success. These data provide a same-donor single-cell atlas of T cell diversity and adaptation across the human gut-liver-blood axis.
    Keywords:  CP: immunology; T cell clonality; clonal distribution; colon intraepithelial lymphocytes; gut-liver-blood axis; lamina propria T cells; multimodal niche inference; single-cell RNA-seq; single-cell TCR sequencing; tissue-resident memory T cells; tissue-specific adaptation
    DOI:  https://doi.org/10.1016/j.celrep.2025.116916
  18. J Exp Med. 2026 Apr 06. pii: e20250005. [Epub ahead of print]223(4):
    Zbtb32 promotes CD8+ T cell differentiation and function in cancer.
    Birui Pan, Qinli Sun, Ruifeng Li, Juan Feng, Jing Hao, Bowen Xie, Xiaohong Zhao, Zixuan Zhao, Peng Wei, Qiuyan Lan, Shiyuan Xie, Tian Xie, Yongzhen Chen, Kun Wei, Xuan Zhong, Hai Qi, Ling Ni, Chen Dong.
      In the tumor microenvironment (TME), "exhausted" CD8+ T cells are classified into progenitor (Tpex) and terminally exhausted (Ttex) populations. Tpex cells, critically regulated by zinc finger and BTB domain containing 27 (Zbtb27)/Bcl6 transcription factor, could be reinvigorated during immune checkpoint blockade (ICB) therapy, while Ttex cells, characterized by stronger proliferation and cytotoxicity, play an indispensable role in tumor control. However, the mechanisms governing the differentiation into Ttex and their function remain not well understood. In this study, we identified that Zbtb32, highly expressed in CD8+ Ttex subset, is crucial for CD8+ T cells within tumors. Zbtb32, regulated by CD28 signaling, promotes the differentiation of CD8+ T cells into Ttex subset, enhancing their cytotoxicity, proliferation, and anti-tumor capability. Importantly, we found a competitive DNA binding between Zbtb32 and Bcl6, especially in regulation of Id2 expression. Thus, our findings demonstrate the pivotal role of Zbtb32 in CD8+ T cell anti-tumor function, with implications in cancer immunotherapy.
    DOI:  https://doi.org/10.1084/jem.20250005
  19. J Immunother Cancer. 2026 Feb 04. pii: e013520. [Epub ahead of print]14(2):
    Dysregulated expression of the tumor suppressor p14ARF in cancer provides an effective target for TCR-T cell therapeutics.
    Thomas M Schmitt, Kelsey Furiya, Cheryl Black, Angie Vazquez, Jaishree Sharma, Menna Hailemariam, Daniel H Paushter, Lam Trieu, Jennifer Lam, Bo Lee, Kavya Rakhra, Kerry A Whalen, Naveen K Mehta, Karsten Sauer, Patrick A Baeuerle, Jennifer S Michaelson, Philip D Greenberg, Aude G Chapuis.
       BACKGROUND: The CDKN2A gene encodes two canonical tumor suppressors, p16INK4A and p14ARF, which safeguard cells from malignant transformation by inducing cell cycle arrest and apoptosis in response to aberrant growth signals. Paradoxically, many cancers overexpress these proteins when downstream effectors that enforce negative feedback regulation are lost or inactivated. For example, p14ARF, which regulates p53 activation, is aberrantly expressed in more than 50% of tumors with inactivating p53 mutations. Here, we evaluated the feasibility of targeting dysregulated p16INK4A and p14ARF expression using TCR-T cell therapeutics.
    METHODS: We analyzed a panel of p16INK4A- and p14ARF-derived peptides for HLA-A*02:01-associated presentation and recognition by CD8+ T cells. Antigen-specific T cell receptors were isolated from healthy donor repertoires and expressed in primary T cells to assess specificity, functional avidity, tumor recognition, and safety using in vitro T cell functional assays, in vivo tumor models, and an in vivo safety model.
    RESULTS: We identified a unique and well-presented p14ARF epitope that was consistently detected in the HLA-A*02:01-associated immunopeptidome of cancer biopsies but not in normal tissues. High-avidity ARF-specific TCRs were isolated from the peripheral repertoire of healthy donors, and TCR-transduced T cells mediated potent tumor cell killing in vitro and in vivo in preclinical models. Furthermore, targeting p14ARF-expressing cells did not result in detectable on-target toxicity in an in vivo safety model.
    CONCLUSIONS: These findings demonstrate the feasibility of targeting dysregulated tumor suppressor proteins with TCR-T cell therapeutics and identify p14ARF as a promising target for future therapies.
    Keywords:  Immunotherapy; Solid tumor; T cell; T cell Receptor - TCR
    DOI:  https://doi.org/10.1136/jitc-2025-013520
  20. Int J Clin Oncol. 2026 Feb 01.
    CD8/CD4 ratio, CD56, and PD-L1 as prognostic markers in sinonasal mucosal melanoma.
    Chiau-Sheng Jang, I-Chieh Chuang.
       BACKGROUND: Sinonasal mucosal melanoma (SNMM) is an aggressive malignancy with limited prognostic markers. This study aimed to determine whether immune markers, including the CD8 to CD4 lymphocyte ratio, CD56-positive lymphocytes, and PD-L1 expression, provide prognostic information beyond established clinicopathological factors.
    METHODS: We retrospectively reviewed 67 patients with surgically treated SNMM at two tertiary medical centers in Taiwan between 2004 and 2023. Standard histopathologic parameters and immunohistochemical assessments of the CD8/CD4 ratio, CD56-positive lymphocytes, and PD-L1 expression in tumor and stromal immune cells were evaluated. Disease-specific survival (DSS) and recurrence-free survival (RFS) were analyzed using Kaplan-Meier estimates and multivariable Cox proportional hazards models.
    RESULTS: The median patient age was 62 years, and 60% were male. During a median follow-up of 42 months, 63% of patients experienced recurrence, and 54% died of the disease. An increased CD8/CD4 ratio and the presence of CD56-positive lymphocytes were associated with better DSS (5-year DSS, 64.3% vs. 32.1% and 70.1% vs. 35.8%, respectively), whereas PD-L1 positivity was associated with shorter RFS (5-year RFS, 28.6% vs. 54.3%). In multivariable analysis, mitotic activity of ≥ 10/mm2 (hazard ratio [HR] 2.31, 95% confidence interval [CI] 1.12-4.78) and PD-L1 positivity (HR 1.92, 95% CI 1.01-3.67) independently predicted worse outcomes, while an increased CD8/CD4 ratio remained associated with improved DSS (HR 0.48, 95% CI 0.23-0.99).
    CONCLUSIONS: Immune markers, particularly the CD8/CD4 ratio and CD56-positive lymphocytes, were significantly associated with survival outcomes independent of traditional histopathologic factors. Incorporating immune profiling into risk stratification may improve prognostication and guide the development of immune-targeted strategies in SNMM.
    Keywords:  CD4; CD56 antigen; CD8 ratio; Infiltrating lymphocytes; Ligand 1; Melanoma; Programmed death; Tumor
    DOI:  https://doi.org/10.1007/s10147-026-02973-9
  21. bioRxiv. 2026 Jan 13. pii: 2026.01.12.699051. [Epub ahead of print]
    NR4A1 limits CD8 + T Cell effector responses and protection in tuberculosis.
    Samreen Fatima, Yao Chen, Lorissa Smulan, Basanthi Satish, Mike Jameson, Sheetal Saini, Calvin Johnson, Alicia Tay, Shihui Foo, Hedayathulla Rahmathulla, Akhila Balachander, Shanshan W Howland, Hardy Kornfeld, Amit Singhal.
      During Mycobacterium tuberculosis ( Mtb ) infection, CD8 + T cells exhibit dysfunction with impaired cytotoxicity and limited localization to granuloma cores. Using knockout mice, adoptive-transfer models and validation in macaque and human datasets, we identified the nuclear receptor NR4A1 as a key restrainer of CD8 + T cell immunity in tuberculosis (TB). Mtb -infected Nr4a1 -/- mice displayed reduced bacterial burden, attenuated pathology, higher lung CD8 + /CD4 + T cell ratios, and enhanced CD8 + T cell effector functions. Bulk and single-cell RNA sequencing revealed suppression of gene expression program linked with exhaustion, and expansion of Nkg7 + and Granzyme + cytotoxic CD8 + T cell subsets in Nr4a1 -/- mice. Spatial analyses demonstrated increased infiltration of Nkg7 + activated CD8 + T cells in Nr4a1 -/- lesions. ChIP-qPCR showed NR4A1 binding to Nkg7 promoter, and Nkg7 knockdown abrogated the enhanced cytotoxicity of Nr4a1 -/- CD8 + T cells. Pharmacologic inhibition of NR4A1 reduced Mtb burden and pathology, and restored Nkg7 expression and CD8 + T cell infiltration in the lung. Together, these findings identify NR4A1 as a negative regulator of CD8 + T cell-mediated immunity in TB and suggest the NR4A1-NKG7 axis as a novel host-directed therapeutic target.
    A one-sentence summary of your paper: NR4A1 suppresses CD8 + T cell infiltration and cytotoxicity in TB lesions, and its inhibition enhances host resistance to Mtb infection.
    DOI:  https://doi.org/10.64898/2026.01.12.699051
  22. Front Immunol. 2025 ;16 1739154
    Macrophage-derived chemokines in T cell regulation: implications for cancer immunotherapy.
    Kunpeng Zhang, Jingjing Liu, Qi Liu, Ningning Zhu, Baodong Ye.
      Macrophages are pivotal regulators of immunity, with intercellular communication being a central mechanism of their function. Among these communications, chemokines act as critical messengers in macrophage-T cell crosstalk. This review systematically elucidates the notable roles of macrophage-derived chemokines in modulating T cell homeostasis, particularly concentrating on their influence on both CD4+ and CD8+ T cell differentiation, proliferation, exhaustion, secretory activity, metabolic reprogramming (involving glycolysis and OXPHOS), chemotaxis, and memory formation. In the tumor microenvironment (TME), the dualistic nature of chemokines was highlighted: tumor-associated macrophages (TAMs) could secrete immunosuppressive factors, such as CCL22 and CCL5, recruiting inhibitory cells and inducing CD8+ T cell exhaustion. In contrast, M1-like macrophages could produce CXCL9 and CXCL10, activating effector CD8+ T cells, thereby enhancing anti-tumor immunity. Finally, the promising therapeutic potential of targeting specific chemokine signaling axes, such as CCL2/CCR2 and CXCL10/CXCR3, was discussed as a strategy to improve the efficacy of cancer immunotherapy.
    Keywords:  T cells; cancer immunotherapy; chemokines; macrophages; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1739154
  23. Nature. 2026 Feb 04.
    Atlas-guided discovery of transcription factors for T cell programming.
    H Kay Chung, Cong Liu, Anamika Battu, Alexander N Jambor, Brandon M Pratt, Fucong Xie, Brian P Riesenberg, Eduardo Casillas, Ming Sun, Elisa Landoni, Yanpei Li, Qidang Ye, Daniel Joo, Jarred Green, Zaid Syed, Nolan J Brown, Matthew Smith, Shixin Ma, Shirong Tan, Brent Chick, Victoria Tripple, Z Audrey Wang, Jun Wang, Bryan Mcdonald, Peixiang He, Qiyuan Yang, Timothy Chen, Siva Karthik Varanasi, Michael LaPorte, Thomas H Mann, Dan Chen, Filipe Hoffmann, Josephine Ho, Jennifer Modliszewski, April Williams, Yusha Liu, Zhen Wang, Jieyuan Liu, Yiming Gao, Zhiting Hu, Ukrae H Cho, Longwei Liu, Yingxiao Wang, Diana C Hargreaves, Gianpietro Dotti, Barbara Savoldo, Jessica E Thaxton, J Justin Milner, Susan M Kaech, Wei Wang.
      CD8+ T cells differentiate into diverse states that shape immune outcomes in cancer and chronic infection1-4. To define systematically the transcription factors (TFs) driving these states, we built a comprehensive atlas integrating transcriptional and epigenetic data across nine CD8+ T cell states and inferred TF activity profiles. Our analysis catalogued TF activity fingerprints, uncovering regulatory mechanisms governing selective cell state differentiation. Leveraging this platform, we focused on two transcriptionally similar but functionally opposing states that are critical in tumour and viral contexts: terminally exhausted T (TEXterm) cells, which are dysfunctional5-8, and tissue-resident memory T (TRM) cells, which are protective9-13. Global TF community analysis revealed distinct biological pathways and TF-driven networks underlying protective versus dysfunctional states. Through in vivo CRISPR screening integrated with single-cell RNA sequencing (in vivo Perturb-seq) we delineated several TFs that selectively govern TEXterm cell differentiation. We also identified HIC1 and GFI1 as shared regulators of TEXterm and TRM cell differentiation and KLF6 as a unique regulator of TRM cells. We discovered new TEXterm-selective TFs, including ZSCAN20 and JDP2, with no previous known function in T cells. Targeted deletion of these TFs enhanced tumour control and synergized with immune checkpoint blockade but did not interfere with TRM cell formation. Consistently, their depletion in human T cells reduces the expression of inhibitory receptors and improves effector function. By decoupling exhaustion TEX-selective from protective TRM cell programmes, our platform enables more precise engineering of T cell states, accelerating the rational design of more effective cellular immunotherapies.
    DOI:  https://doi.org/10.1038/s41586-025-09989-7
  24. Cell Immunol. 2026 Feb 02. pii: S0008-8749(26)00005-5. [Epub ahead of print]419 105065
    Ibrutinib enhances stem-cell-memory T cell generation during early T cell activation but inhibits T cell proliferation.
    Ling He, Yifei Liu, Junjie Zhou, Taiyan Zhang, Shihao Zhang, Jian Ge, Jian Hong.
      Ibrutinib has been demonstrated to restore T cell immunity of chronic lymphocytic leukemia patients, and enhance ex vivo expansion and function of CAR-T cells. In attempt to explore the effect of ibrutinib on unmanipulated T cells, we activated human PBMCs from healthy donors with CD3/CD28 stimulation and cultured them with or without ibrutinib under various conditions. Phenotypic and functional assessments were then performed using flow cytometry. Results showed that ibrutinib could downregulate programmed cell death protein 1 expression and reduce activation-induced cell death of T cells. Additionally, ibrutinib added at the onset of T cell activation, rather than 48 h later, could further promote the generation of CD45RA+CCR7+CD95+ stem-cell-memory T cell subset in the presence of IL-7 and IL-15. However, ibrutinib also suppressed the proliferation and cytokine-secretion capacity of T cells in a dose-dependent manner. Further RNA sequencing of activated CD8+ T cells demonstrated that ibrutinib administration at the onset of T cell activation modulated multiple TCR downstream signaling pathways, notably downregulating mTORC1 signaling and upregulating FOXO1 signaling. In contrast, ibrutinib added 48 h post-activation did not show these effects. These findings suggest that caution should be exercised when incorporating ibrutinib into ex vivo expansion system for adoptive non-genetically engineered T cells or combining ibrutinib with these T cell immunotherapies in clinical trial settings.
    Keywords:  Activation-induced cell death; Cytokine-secretion capacity; Ibrutinib; Proliferation; T cell; Tscm cell phenotype
    DOI:  https://doi.org/10.1016/j.cellimm.2026.105065
  25. Int Immunopharmacol. 2026 Feb 01. pii: S1567-5769(26)00108-6. [Epub ahead of print]173 116265
    Autophagy-driven CCL7+ monocyte terminal differentiation program fuels CD8+ T cell-mediated cardiac injury in Sepsis.
    Xueyi Sun, Shaolei Geng, Zeyuan Wang, Qingjiang Chen.
       OBJECTIVE: Sepsis-induced cardiomyopathy (SCM) is a life-threatening complication with poorly understood immune-metabolic drivers. This study aims to uncover the role of autophagy-dependent monocyte reprogramming and its contribution to myocardial injury via CCL7-mediated immune activation in sepsis.
    METHODS: We performed integrated analysis of bulk and single-cell transcriptomic data from septic patients (GSE65682, GSE152363, GSE167363). Autophagy activity and chemokine signaling were evaluated using bioinformatic approaches including WGCNA, pseudotime trajectory inference, and CellChat communication analysis. Functional validation was conducted through in vitro co-culture systems and in vivo models of LPS-induced sepsis, utilizing CCL7 neutralization, flow cytometry, ELISA, and Western blot.
    RESULTS: Single-cell RNA sequencing revealed a distinct C6 monocyte subset characterized by high autophagic flux, elevated CCL7 expression, and an M1-like inflammatory phenotype. Pseudotime analysis positioned C6 monocytes at the terminal end of monocyte differentiation, where they functioned as chemokine hubs amplifying cross-talk with CD8+ T cells, NK cells, and neutrophils. Mechanistically, CCL7 secretion by C6 monocytes promoted autocrine M1 polarization and enhanced CD8+ T cell activation via CCR1/CCR2-dependent PI3K-AKT signaling. In co-culture, CCL7-stimulated CD8+ T cells induced oxidative stress, cytokine release, and cardiomyocyte apoptosis. In vivo, CCL7 neutralization alleviated myocardial injury, reduced cardiac ROS accumulation, and suppressed systemic inflammation.
    CONCLUSIONS: Our findings identify a pathogenic autophagy-CCL7-monocyte-T cell axis as a central driver of immuno-metabolic dysregulation in SCM. Targeting CCL7-mediated signaling may represent a novel immunomodulatory strategy to restore cardiac immune homeostasis and mitigate sepsis-induced myocardial injury.
    Keywords:  Autophagy; CCL7; CD8+ T cell activation; Immune-metabolic dysregulation; Monocyte terminal differentiation; Sepsis-induced cardiomyopathy
    DOI:  https://doi.org/10.1016/j.intimp.2026.116265
  26. Cancer Treat Res Commun. 2026 Jan 22. pii: S2468-2942(26)00021-3. [Epub ahead of print]46 101112
    Clinical characteristics and survival outcomes of young women with luminal HER2-low and HER2-ultralow breast cancer.
    Jesus Edgardo Hernandez-Hernandez, César Octavio Lara-Torres, Alejandro Aranda-Gutierrez, Víctor A Domínguez-Porras, Bryan Moreno-Moran, Héctor Díaz-Pérez, Gabriela Sofía Gómez-Macías, Cynthia Villarreal-Garza, Alejandro Mohar.
       BACKGROUND: Young women with breast cancer (YWBC) often present with aggressive, hormone receptor-positive tumors. However, the implications of HER2-low and HER2-ultralow expression in this group have not been well characterized despite their potential therapeutic relevance.
    METHODS: We conducted a retrospective study of 157 Mexican women aged ≤ 40 years with a prior diagnosis of luminal, HER2-negative breast cancer. HER2 status was reassessed to characterize different levels of HER2 expression within HER2-negative disease, specifically HER2-null, HER2-low, and HER2-ultralow. Clinicopathological features and survival outcomes were compared across groups.
    RESULTS: Evaluation of HER2 expression levels identified that 21.0 % of tumors met criteria for HER2-low expression and 18.5 % for HER2-ultralow expression. HER2-low tumors were more prevalent in luminal B disease and were associated with higher Ki-67, lower PR, and increased tumor-infiltrating lymphocytes, while there were no particularities in HER2-null and ultralow tumors. No significant differences were observed in disease-free or overall survival between HER2-null, HER2-low, and HER2-ultralow groups.
    CONCLUSIONS: Approximately 40 % of young women with luminal HER2-negative breast cancers have HER2-low or ultralow disease. These findings highlight the importance of accurately assessing HER2 expression in YWBC to identify candidates for emerging HER2-targeted therapies such as trastuzumab deruxtecan.
    Keywords:  Antibody-drug conjugates; Breast cancer; HER2-low; HER2-ultralow; Young
    DOI:  https://doi.org/10.1016/j.ctarc.2026.101112
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