bims-tuinly 2026-01-11 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2026–01–11
thirty-two papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Targeting highly attenuated IL-18 to PD-1 for enhanced anti-tumor activity.
Prognostic Significance of CD4+ T Cell Transcription Factors in Tumor Microenvironment: Insights from Tumor-Infiltrating Lymphocytes in Breast Cancer.
OX40L and IL-2 combination strategy for gastric cancer immunotherapy.
Single-Cell Dissection of Tumor-Infiltrating Lymphocytes Reveals Cellular Architecture Predictive of Therapeutic Efficacy in Acral Melanoma.
Advancing adoptive T cell therapy in ovarian cancer: barriers, innovations, and emerging platforms.
Enrichment of CD103⁺CD4⁺ T Cells in Bone Metastases Compared to Non-Malignant Controls.
Prognostic relevance of specific TIL (CD4+, CD8+, and FOXP3 + T-cell infiltrates) in triple-negative breast cancer: short- and long-term outcomes.
TMEM33 deletion potentiates anti-tumor CD8 + T cell immunity.
DNA Methylation in Lung Cancer: Predictive Biomarkers for Effective Immunotherapy.
A CD8αβ co-receptor modified to contain an intracellular CD28 signaling tail enhances TCR-engineered T cell function independent of solid-tumor-associated co-stimulatory ligands.
Effects of Vemurafenib ± Cobimetinib on Intratumoral and Host Immunity in Patients With BRAFV600 Mutant Melanoma: Implications for Combination With Immunotherapy.
Research Progress of Radiotherapy Combined With Immunotherapy for Breast Cancer: Mechanism Exploration and Clinical Translation.
ADA1-Driven Metabolic Refueling Enhances CAR T Cell Therapy for Solid Tumors.
Advancing Cancer Immunotherapy: Chimeric Antigen Receptor (CAR)-T Cell Engineering through Novel Screening Methods.
PD-1 regulates CD4+ T cell-mediated CD8+ T cell responses in the brain to balance viral control and neuroinflammation.
IL-21 enhances the cytotoxicity of intratumoral CD8+ T cells improving radiation efficacy.
SAA restricts T cell mediated anti-tumor immunity by limiting antigen presentation in lung cancer.
TPP-45142-an Anti-HER2 T cell Engager-Designed for Selective HER2-Low Cancer Immunotherapy.
Systemic immune-inflammation index prior to postoperative radiotherapy as a tool for outcome prediction in thymic epithelial tumors.
Engineering T Cells with Membrane-Anchored Nitric Oxide Scavengers for Anticancer Therapy.
Macrophage-Dendritic Cell-T-Cell Tetrads Orchestrate Antitumor Immunity and Response to Checkpoint Blockade.
Conversion therapy using transarterial chemoembolization plus tislelizumab for unresectable hepatocellular carcinoma: effects on tumor necrosis and anti-tumor immune response.
Adaptive Immunity and Alzheimer's Disease: Dual Roles in Neurodegeneration and Neuroprotection with Therapeutic Implications.
Loss of ARID1A expression is associated with worse survival and reduced tumor infiltrating lymphocytes in advanced clear cell renal cell carcinoma.
Prognostic Role of Mitotic Index in Hepatocellular Carcinoma: Potential Clinical Implications for Very Early Stage Disease.
TIGIT disruption rescues the antitumor activity of low avidity TCR-engineered T cells by increasing TCR signal strength.
Improved prognostic predictability of the latest Japanese TNM Classification in patients undergoing resection for distal cholangiocarcinoma.
Development and validation of the APTNM staging system: Integration of serum biomarkers with TNM classification for enhanced prognostic stratification following hepatectomy for hepatocellular carcinoma.
The LXRβ/NF-κB axis reprograms CAR-T cells to resist exhaustion in the tumor microenvironment.
Brain-infiltrating CD8 T cells retain functional activity to protect against acute Zika virus infection.
Design, Development, and Characterization of a Tannic Acid-loaded Transfersomal Gel for Psoriatic Skin.
CLDN18.2 in Gastric Cancer: Current Therapeutic Landscape and Future Perspectives.

Front Immunol. 2025 ;16 1718321

Targeting highly attenuated IL-18 to PD-1 for enhanced anti-tumor activity.

Xueyuan Zhou, Felix Klaus Geyer, Jeffrey Takimoto, Harald Kolmar, Brian Rabinovich.

  Checkpoint inhibitors targeting the PD-1/PD-L1 axis have revolutionized cancer immunotherapy, yet response rates remain limited. To enhance efficacy, next-generation approaches target T cell-activating cytokines to PD-1 via antibodies. The goal is simultaneous checkpoint blockade and cytokine potentiation but fine-tuning cytokine activity such that checkpoint inhibition can be preserved with manageable toxicity has been a difficult challenge. We hypothesized that targeting a highly attenuated interleukin (IL)-18 to PD-1 can activate PD-1+ T cells and oppose exhaustion while antagonizing PD-1. We generated a highly attenuated IL-18 variant, which is resistant to IL-18BP binding and assessed its receptor binding ability. Tumor growth inhibition was evaluated across multiple models. Additionally, we examined post-remission tumor resistance and lymphocyte infiltration into the tumor ex vivo using flow cytometry. The IL-18 fusion resisted interleukin-18 binding protein (IL-18BP) inhibition and exhibited a 10,000-fold reduction in activity while preserving cis-signaling and demonstrated strong efficacy across tumor models. It increased CD8+ progenitor-exhausted tumor-infiltrating lymphocytes (TILs) while reducing myeloid TILs. Attaching a highly attenuated IL-18 to an anti-PD-1 antibody goes beyond simply targeting a cytokine to PD-1, representing a novel cytokine-enhanced checkpoint inhibitor that activates PD-1+ T cells via the cytokine receptor while simultaneously antagonizing PD-1.

Keywords:  IL-18; PD-1; checkpoint inhibitor; cytokine; immunocytokine

DOI:  https://doi.org/10.3389/fimmu.2025.1718321
Cancer Invest. 2026 Jan 05. 1-11

Prognostic Significance of CD4+ T Cell Transcription Factors in Tumor Microenvironment: Insights from Tumor-Infiltrating Lymphocytes in Breast Cancer.

Maryam Rezaee, Fatemeh Kheiri, Rasoul Baharlou, Nahid Nafissi.

  The tumor microenvironment (TME) influences breast cancer progression through immune system interactions, particularly by affecting the differentiation of CD4+ T cells. This study aims to explore how the TME affects the expression of transcription factors-Foxp3, RORγt, GATA3, and T-bet-in tumor-infiltrating lymphocytes (TILs) and their implications for clinical outcomes. Forty-eight breast cancer patients were enrolled. Tumor tissues were collected, and quantitative real-time PCR was performed to assess the expression of transcription factors. Patients with positive lymphovascular invasion (LVI) and high tumor grades exhibited significantly elevated Foxp3 expression. In contrast, RORγt expression decreased in patients with advanced disease. GATA3 levels correlated positively with LVI, tumor grade and advanced tumor stages, while T-bet expression was lower in patients with positive LVI, positive lymph node and larger tumor sizes. Multivariate analysis identified RORγt as a risk factor for lymph node involvement and stage of disease, while GATA3 emerged as a protective factor. Receiver operating characteristic (ROC) analysis demonstrated GATA3's potential for late-stage detection, and RORγt as a reliable staging marker. Our findings highlight the critical role of TIL-derived transcription factors in breast cancer progression and their potential as prognostic biomarkers, emphasizing the importance of TME-mediated T cell differentiation in shaping disease outcomes.

Keywords:  Breast cancer; Foxp3; GATA3; RORγt; T-bet; TIL

DOI:  https://doi.org/10.1080/07357907.2025.2608139
Transl Cancer Res. 2025 Dec 31. 14(12): 8807-8824

OX40L and IL-2 combination strategy for gastric cancer immunotherapy.

Benshun Hu, Emanuela Garbarino, Jingjing Ma, Chengyuan Yan, Junli Jia, Hua Xie, Lingyun Li, Cheng Jin, Yuzheng Xue, Huamin Tang.

   Background: Gastric cancer (GC) remains a major global health challenge with persistently low remission rates, largely because most patients are diagnosed at advanced stages. Although chemotherapy, targeted therapy, and immune checkpoint inhibitors have achieved progress, their benefits remain limited due to the highly immunosuppressive tumor microenvironment (TME), characterized by inadequate T-cell activation and impaired costimulatory signaling. Recent genomic and single-cell studies highlight the need for strategies that can more effectively enhance antitumor immunity. Given these challenges, this study aimed to evaluate whether dual stimulation with interleukin-2 (IL-2) and OX40 ligand (OX40L) could synergistically enhance T-cell activation in GC. Specifically, we analyzed OX40/OX40L expression patterns in GC tissues and tumor-infiltrating lymphocytes (TILs), assessed the immunostimulatory effects of IL-2 and OX40L in PBMCs and TILs, and tested a recombinant adenoviral vector co-expressing IL-2 and OX40L to determine its ability to potentiate T-cell-mediated cytotoxicity against primary GC tumor cells.
Methods: Based on preliminary analyses of The Cancer Genome Atlas (TCGA) database and single-cell RNA sequencing (scRNA-seq) data, we identified the costimulatory molecules IL-2 and OX40L as potential therapeutic targets. We collected tumor tissues and paired peripheral blood mononuclear cells (PBMCs) from 70 untreated GC patients, and used bioinformatics tools to analyze T cell subpopulations and OX40/OX40L expression in the TME. The immunostimulatory effects of IL-2 and OX40L, used alone or in combination, were evaluated in vitro on PBMCs and TILs. A recombinant adenoviral vector co-expressing IL-2 and OX40L was also constructed to assess its pro-apoptotic effect in primary GC tumor cell cultures.
Results: The combination of IL-2 and OX40L significantly enhanced T cell activation in both PBMCs and TILs, and increased the expression of antitumor effector molecules. The IL-2/OX40L adenoviral vector effectively activated TILs, which subsequently induced prominent apoptotic responses in primary GC tumor cells.
Conclusions: Our study demonstrates that a costimulatory immunotherapy strategy combining IL-2 and OX40L significantly enhances antitumor responses in PBMCs and TILs from GC patients, showing strong therapeutic potential as a complementary approach for the treatment of GC.

Keywords:  Gastric cancer (GC); OX40 ligand (OX40L); immunotherapy; interleukin-2 (IL-2); tumor-infiltrating lymphocytes (TILs)

DOI:  https://doi.org/10.21037/tcr-2025-707
Adv Sci (Weinh). 2026 Jan 04. e21555

Single-Cell Dissection of Tumor-Infiltrating Lymphocytes Reveals Cellular Architecture Predictive of Therapeutic Efficacy in Acral Melanoma.

Chao Zhang, Wanyi Xiao, Hongru Shen, Fenge Li, Ting Li, Weihong Zhang, Haotian Liu, Ziwei Gao, Hongyu Wang, Xiubao Ren, Kexin Chen, Xiangchun Li, Jilong Yang.

  Acral melanoma (AM), the predominant melanoma subtype in Asia, responds poorly to immune checkpoint inhibitors, representing a critical unmet medical need. The efficacy of tumor-infiltrating lymphocyte (TIL) therapy in this population is unknown. An Investigator-Initiated Trial evaluates autologous TIL therapy (LM-103) in four Chinese patients with advanced AM, achieving a 75% disease control rate (DCR) and a 25% objective response rate (ORR), including one durable complete response. To define the determinants of response, we performed integrated single-cell RNA and T-cell receptor sequencing on infused TIL products, tumors, and longitudinal peripheral blood. Responders' infused products were significantly enriched for T follicular helper (Tfh) and intermediate exhausted (TEX_int) CD8⁺ T cells, which mediated robust cell-cell signaling networks (e.g., CD40, FASLG). In contrast, the non-responder's product was dominated by terminally exhausted (TEX_term) cells. Clonal tracking revealed that these Tfh and TEX_int subsets possessed higher clonality, and in the complete responder, a dominant clone originating from the TEX_int population persisted systemically by differentiating into a progenitor-like (TEX_prog) state. These findings demonstrate that TIL therapy is clinically active in AM and that durable response is mechanistically linked to the infusion and persistence of Tfh and TEX_int subsets, defining a key cellular and clonal architecture for therapeutic success.

Keywords:  Clonal expansion; TEX_int; TIL therapy; Tfh; acral melanoma; scRNA‐seq & scTCR‐seq

DOI:  https://doi.org/10.1002/advs.202521555
J Immunother Cancer. 2026 Jan 09. pii: e013285. [Epub ahead of print]14(1):

Advancing adoptive T cell therapy in ovarian cancer: barriers, innovations, and emerging platforms.

Gabriel Nascimento De Souza Santos, Celia DeJohn, Suzanne M Hess, Emese Zsiros, A J Robert McGray.

  Adoptive cell therapy (ACT) has demonstrated curative potential in select cancers, but its translation to solid tumors such as ovarian cancer (OC) has been hindered by multiple factors, including tumor heterogeneity, immune exclusion, and a profoundly immunosuppressive tumor microenvironment. This review provides a comprehensive analysis of current ACT modalities, including tumor-infiltrating lymphocytes, T cell receptor-engineered, and chimeric antigen receptor-T cell therapies, as well as emerging approaches such as bispecific T cell engager (BiTE)-secreting T cells, dual-targeting platforms, and synthetic antigen receptors. We examine their application in OC and contextualize relevant findings using insights from other solid tumors. Key barriers, including limited T cell persistence, antigen escape, and T cell exhaustion, are explored alongside strategies to enhance efficacy through cytokine armoring, checkpoint modulation, metabolic reprogramming, and gene editing. We further highlight innovations in safety engineering, including logic-gated and self-regulating synthetic circuits, to mitigate toxicity and improve precision. Additional attention is given to the evolving role of allogeneic products and in vivo engineering as scalable solutions. Finally, we emphasize the critical value of integrating high-dimensional tools such as spatial transcriptomics, single-cell profiling, and machine learning to refine ACT design, identify biomarkers of response, and support patient selection and stratification. Collectively, these advances offer a roadmap for overcoming the unique immunologic barriers to ACT in OC and accelerating the development of more potent, durable, and personalized T cell-based strategies.

Keywords:  Adoptive cell therapy - ACT; Bispecific T cell engager - BiTE; Chimeric antigen receptor - CAR; Ovarian Cancer; Tumor infiltrating lymphocyte - TIL

DOI:  https://doi.org/10.1136/jitc-2025-013285
Immunol Lett. 2026 Jan 02. pii: S0165-2478(26)00008-8. [Epub ahead of print] 107135

Enrichment of CD103⁺CD4⁺ T Cells in Bone Metastases Compared to Non-Malignant Controls.

Elias Brauneck, Julian Kylies, Anne Marie Assemissen, Moritz Kruppa, Niklas Kruppa, Yagana Wahid, Franziska Brauneck, Walter Fiedler, Lennart Viezens, Jasmin Wellbrock, Leon-Gordian Leonhardt.

   BACKGROUND: Bone metastasis (BoM) is a frequent complication of solid tumors, leading to poor prognosis and reduced survival. CD103⁺ tumor-infiltrating lymphocytes (TILs) are critical for antitumor immunity, yet studies have largely focused on CD8⁺ subsets, leaving CD103⁺CD4⁺ cells poorly characterized.
METHODS: Bone aspirates containing malignant cells were obtained from patients with symptomatic spinal and/or pelvic metastases of breast cancer (BC), prostate cancer (PC), or non-small cell lung cancer (NSCLC). Age-matched bone marrow samples from individuals without malignancy (NMCs) were controls. Multiparametric flow cytometry (MFC) was utilized to assess the expression of CD103 and exhaustion markers (TIGIT, PVRIG, KIR2DL5, CD39) in CD3+ cells.
RESULTS: CD103⁺CD3+ T cells are significantly elevated in BoM compared to NMC, driven by an increase in CD103⁺CD4⁺ cells, despite a relative decrease in frequency of CD103⁺CD8⁺ cells. Furthermore, CD103+CD4+ T cells from BoM displayed a significantly increased fraction of the central memory (CM) phenotype. Expression and co-expression of TIGIT, PVRIG, KIR2DL5 and CD39 on CD103+ cells both in the CD4 and CD8 compartment was significantly increased in BoM, compared within CD103- within BoM and CD103+ in NMC.
CONCLUSION: In conclusion, BoM exhibit a distinct T-cell composition, highlighted by an increase in CD103⁺CD4⁺ T cells displaying an increased CM phenotype. In BoM, coregulatory receptor expression is increased on CD103⁺ T cells, with distinct co-expression signatures in both CD4⁺ and CD8⁺ cells. Functional studies will determine whether targeting these checkpoint pathways can improve immunotherapy for metastatic bone disease.

Keywords:  Bone metastasis; T cells; TIGIT axis; anti-tumor immunity; checkpoint molecules; purinergic signaling

DOI:  https://doi.org/10.1016/j.imlet.2026.107135
Breast Cancer. 2026 Jan 07.

Prognostic relevance of specific TIL (CD4+, CD8+, and FOXP3 + T-cell infiltrates) in triple-negative breast cancer: short- and long-term outcomes.

Olga Caramelo, Vânia Almeida, Ana Fidalgo, Augusta Cipriano, Teresa Almeida-Santos.

   BACKGROUND: Breast cancer is a heterogeneous malignant disease that remains as one of the most prevalent cancers globally. Triple negative breast cancer (TNBC) accounts for 15% of the total of breast cancers and presents high tumor immunogenicity and a tumor microenvironment that plays a critical role in disease progression and patient outcomes.
METHODS: This study evaluated a total of 30 tissue samples from female patients with TNBC, to characterize specific immune cells within the tumor tissue and investigate their relationship with short (pathological complete response, pCR), long (disease-free survival, DFS) and clinical outcomes. Tumor-infiltrating lymphocytes (TIL) were assessed by immunohistochemistry (IHC) on tissue microarrays (TMA), complemented by digital analysis for standardized quantification.
RESULTS: Our results highlight the influence of CD4⁺ T cells on short-term outcomes: high CD4⁺ T-cell levels were significantly associated with achieving pCR. High CD8⁺ T-cell levels were also significantly associated with axillary lymph node negativity.Regarding long-term outcomes, higher CD4⁺, CD8⁺ and FOXP3⁺ T-cell levels showed a non-significant tendency toward improved DFS.
CONCLUSIONS: These findings suggest that high levels of CD4 + T cells and CD8 + T cells are positive predictors of immediate, long-term prognosis and clinical prognosis in patients with TNBC. This study enhances the understanding on the immunological interests in specific subtypes of TIL and identifies potential biomarkers that could drive advancements in precision medicine for breast cancer management.

Keywords:  Breast cancer; CD4 + T cells; CD8 + T cells; FOXP3 + cells; Immune cells; T cells; T regs; TIL

DOI:  https://doi.org/10.1007/s12282-025-01819-y
bioRxiv. 2026 Jan 02. pii: 2026.01.01.697288. [Epub ahead of print]

TMEM33 deletion potentiates anti-tumor CD8 + T cell immunity.

Matthew T Jackson, Tianming Zhao, Gusztav Milotay, Isabela Pedroza-Pacheco, Yanshu Cai, Claire Willis, Su M Phyu, Bruno Beernaert, Jamie Tw Kwon, Hala Estephan, Vinnycius Pereira Almeida, Maria Aggelakopoulou, Silvia Panetti, Christian Zierhut, Tim Elliott, Eleni Adamopoulou, Jan Rehwinkel, Malcolm Jw Sim, Amit Grover, Dmitry I Gabrilovich, Benjamin P Fairfax, Eric Honoré, David R Withers, John C Christianson, Eileen E Parkes.

Improving responses to cancer immunotherapies requires deeper insight into the cellular mechanisms governing T cell-mediated anti-tumor immunity. TMEM33 is an endoplasmic reticulum-resident transmembrane protein enriched across multiple tumor types, with reported functions in anti-viral immunity as well as calcium and lipid homeostasis, yet its role in tumor immunosurveillance remains unknown. Using murine genetic models, we demonstrate that host TMEM33 constrains anti-tumor CD8 + T cell responses. Constitutive Tmem33 -/- mice exhibited delayed melanoma tumor growth and increased CD8 + T cell infiltration. Antigen-specific CD8 + compartments in tumors of Tmem33 -/- mice showed TCF-1 + PD-1 + progenitor-exhausted cell (Tpex) enrichment, elevated effector function and reduced exhaustion, alongside improved effector memory expansion and T-bet expression in draining lymph nodes. We highlight that TMEM33 functions intrinsically within the T cell compartment, as TMEM33 deletion (1) enhanced polyclonal activation of naive CD8 + T cells ex vivo , (2) promoted preferential Tpex accumulation among adoptively transferred naive OT-I cells in B16F10-OVA tumors and draining lymph nodes, and (3) improved the potency of ex vivo -expanded OT-I cells in controlling tumor growth during adoptive cell therapy. Finally, in a large, prospectively recruited metastatic melanoma cohort, lower TMEM33 expression in patient CD8 + T cells significantly correlated with improved survival and elevated TCF-7 (encoding TCF-1). Collectively, our findings define TMEM33 as a formerly unrecognized intrinsic determinant of tumor-directed CD8 + T cell fate that limits Tpex maintenance, and restrains cell therapy responses, suggesting that its modulation may strengthen immunotherapeutic efficacy.
One sentence summary: TMEM33 intrinsically limits progenitor exhausted CD8 + T cells, scales anti-tumor responses and predicts melanoma patient survival.

DOI: https://doi.org/10.64898/2026.01.01.697288
Int J Gen Med. 2025 ;18 7893-7910

DNA Methylation in Lung Cancer: Predictive Biomarkers for Effective Immunotherapy.

Komal Kumari, Vinay Kumar, Chaitenya Verma, Ping-Ching Hsu, Amarnath Singh.

  Lung cancer remains a leading cause of cancer-related mortality worldwide, and immunotherapy has emerged as a promising treatment modality. However, its efficacy is limited to a subset of patients, necessitating predictive biomarkers for personalized treatment strategies. DNA methylation (DNAm) is increasingly recognized as a crucial regulators of gene expression and immune responses in the tumor microenvironment. This review focuses on DNAm as a key epigenetic biomarker for predicting and enhancing immunotherapy efficacy in lung cancer. We highlight DNAm changes in key immune-related genes and their association with tumor phenotype, immune cell infiltration, and response to immune checkpoint inhibitors (ICIs). The review also evaluates established and emerging genomic and non-genomic biomarkers, including tumor mutational burden (TMB), microsatellite instability (MSI), PD-L1 expression, tumor-infiltrating lymphocytes (TILs), and immunosuppressive cytokines in case of lung cancer immunotherapy. Furthermore, the potential for integrated epigenetic signatures and minimally invasive diagnostic approaches, such as liquid biopsies, is discussed. Finally, we address the challenges and future directions for translating epigenetic biomarkers into clinical practice to improve immunotherapy outcomes and reduce immune-related adverse events.

Keywords:  epigenetic biomarkers; immunotherapy; microsatellite instability; tumor microenvironment; tumor mutational burden; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.2147/IJGM.S552594
Nat Commun. 2026 Jan 03.

A CD8αβ co-receptor modified to contain an intracellular CD28 signaling tail enhances TCR-engineered T cell function independent of solid-tumor-associated co-stimulatory ligands.

Shihong Zhang, Tzu-Hao Tang, Sinéad Kinsella, Francesco Mazziotta, Michael T Schweizer, Megan S McAfee, Ariunaa Munkhbat, Yapeng Su, Valentin Voillet, Lauren E Martin, Colton W Smith, Yuta Asano, Menna Hailemariam, Jakob Bakhtiari, Bo Lee, Cecilia Yeung, Hung Chen, Alessandro M Rizzi, Daniel G Chen, Kelsey Furiya, Nick Horst, Tianzi Zhang, Phung Le, Kelly McKenna, Shannon K Oda, Anthony Rongvaux, Phillip D Greenberg, Thomas M Schmitt, Aude G Chapuis.

Adoptive transfer of T cells engineered with tumor-specific T cell receptors (TCRs) has shown limited efficacy in solid tumors, hindered by insufficient persistence, tumor trafficking, and dependence on tumor-associated co-stimulatory ligands. In a phase I trial (NCT04639245) for patients with metastatic MAGE-A1-expressing tumors and adequate organ function; one participant received treatment, which was well-tolerated. In this case and NSG murine models, infusion of CD4/CD8 T cells co-expressing a class-I MAGE-A1-specific TCR and CD8αβ, failed to control tumor progression. To enhance function downstream of TCR signaling, here we investigate the adaptability of TCR components to synthetic modification. Leveraging the obligate co-expression of CD8αβ required for class-I TCR function in CD4 T cells, we identify CD8β as a tractable site for engineering without loss of function. In vitro screening demonstrates incorporation of the CD28 intracellular tail, yielding a CD8/CD28 chimeric co-receptor, most effectively enhances cytokine production, T cell persistence, and tumor control in immunodeficient murine models while preserving stem-like transcriptional features compared to native CD8β. Further rational modification of the CD28 binding motifs improves tumor control in vivo with increased intratumoral accumulation and reduced exhaustion. This benefit also extends to PRAME and WT1-specific TCRs in vitro supporting generalizability.

DOI: https://doi.org/10.1038/s41467-025-67446-5
Cancer Med. 2026 Jan;15(1): e71526

Effects of Vemurafenib ± Cobimetinib on Intratumoral and Host Immunity in Patients With BRAFV600 Mutant Melanoma: Implications for Combination With Immunotherapy.

Suthee Rapisuwon, Craig L Slingluff, Jennifer A Wargo, Ryan J Sullivan, Benjamin Izar, Jia-Ren Lin, Ileana S Mauldin, Walter C Olson, Christine A Tran, Gabrielle H Schwartzman, Geoffrey T Gibney, Waddah Al-Refaie, Michael B Atkins.

   BACKGROUND: Prior studies in patients with BRAF-mutant melanoma have shown increased density of tumor infiltrating lymphocytes (TIL) after 2 weeks of BRAF (BRAFi) ± MEK inhibition (MEKi), but did not characterize the functional state or clonal diversity of TIL over time. We evaluated sequential tumor biopsies during therapy to test the hypotheses that BRAF/MEKi would increase TIL to day 29, with increases in IFNγ signatures and T-cell homing receptor ligands and expansion of functional intratumoral tumor-reactive CD8 T-cells and TIL clonality in the tumor microenvironment.
METHODS: Subjects with biopsy-accessible BRAF-mutant advanced melanoma received vemurafenib+/-cobimetinib. Tumor biopsies were obtained at baseline and days 8, 15, and 29 on therapy. Tumors were analyzed by quantitative immunofluorescence (QIF), NanoString, and TCRseq.
RESULTS: Five patients were enrolled. All had an initial tumor response followed by subsequent progression. In four patients, both CD8+ and CD4+ TIL density increased by day 8 or 15 per QIF and continued to increase at day 29 in two. Gene expression data showed upregulation of genes/pathways associated with immunologic rejection of cancer, including Class I and II MHC expression, antigen processing/presentation, and critical T-cell attracting chemokines. TCRvβ clonal expansion was observed in 3 patients, but most diminished after day 15.
CONCLUSIONS: Data from this study provides provocative evidence that, while BRAF+/-MEK inhibitor therapy produces an increase in overall and clonal T cell infiltrates, there is limited evidence for generation of new or persistent tumor immunity. Thus, BRAFi/MEKi therapy may enable tumor-reactive T cells to infiltrate tumors but tumor control does not appear to depend on priming new immune responses.

Keywords:  BRAF/MEK inhibitor therapy; melanoma; tumor immune microenvironment

DOI:  https://doi.org/10.1002/cam4.71526
Clin Breast Cancer. 2025 Dec 02. pii: S1526-8209(25)00346-5. [Epub ahead of print]26(2): 1-16

Research Progress of Radiotherapy Combined With Immunotherapy for Breast Cancer: Mechanism Exploration and Clinical Translation.

He Yijun, Lu Huixing, Wang Liping.

  Radiation therapy (RT) dynamically modulates the breast cancer immune microenvironment by inducing immunogenic cell death (ICD) and reshaping the tumor microenvironment. However, RT alone is often insufficient to achieve complete tumor eradication due to compensatory immunosuppressive mechanisms within the tumor microenvironment. The combination of RT with immune checkpoint inhibitors (ICIs) has thus emerged as a potent strategy to overcome these limitations, particularly in triple-negative breast cancer (TNBC).Preclinical studies confirm that radiotherapy fractionation regimens critically influence immune regulation: moderate hypo fractionated doses (eg, 8-12 Gy per fraction) optimally activate the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway and promote CD8+T cell infiltration, whereas single ablative doses exceeding 15 Gy may attenuate immunogenicity by upregulating the DNA exonuclease Trex1. Clinical trials such as PEARL demonstrate that this combination regimen, Stereotactic body radiotherapy (SBRT) with ICIs and neoadjuvant chemotherapy) achieves a pathological complete response (pCR) rate of 59.2% in TNBC patients. Key challenges remain, including optimizing RT-ICI sequencing, managing overlapping toxicities (eg, pneumonitis), and validating predictive biomarkers such as tumor-infiltrating lymphocytes (TILs) and circulating tumor DNA (ctDNA). Future research will focus on integrating AI-driven radiotherapy with multi-omics to address tumor heterogeneity. Targeting immunosuppressive pathways like indoleamine 2,3-dioxygenase1 (IDO1) and histone deacetylase (HDAC) may enhance treatment efficacy. This review synthesizes mechanistic, clinical, and translational advances in radiotherapy-ICI combinations, providing a theoretical foundation and strategic outlook for optimizing precision breast cancer therapy.

Keywords:  Combination therapy; Immune checkpoint inhibitors; Predictive biomarkers; Tumor microenvironment; cGAS-STING pathway

DOI:  https://doi.org/10.1016/j.clbc.2025.11.017
Cancers (Basel). 2025 Dec 22. pii: 34. [Epub ahead of print]18(1):

ADA1-Driven Metabolic Refueling Enhances CAR T Cell Therapy for Solid Tumors.

Alex Wade Song, Xiaotong Song.

  CAR T cell therapy, while highly effective for hematological malignancies, continues to face significant hurdles in the treatment of solid tumors. Key challenges include severe nutrient deprivation and the presence of immunosuppressive metabolites such as adenosine in the tumor microenvironment, which limit CAR T cell persistence and antitumor activity. This review focuses on current progress and future directions for ADA1-based metabolic reprogramming as a targeted approach to enhance CAR T cell function. We discuss recent advances, particularly the engineering of CAR T cells to express ADA1, which facilitates the local conversion of immunosuppressive adenosine into inosine, thereby supporting T cell metabolism and improving therapeutic outcomes. Preclinical studies, including our own, demonstrate that ADA1-expressing CAR T cells exhibit reduced exhaustion, greater metabolic flexibility, and enhanced antitumor efficacy in solid tumor models. The selective clearance of adenosine and supplementation of inosine directly address the metabolic barriers within the tumor microenvironment and provide an effective strategy to bolster CAR T cell responses. Integration of ADA1-driven metabolic refueling with future innovations in CAR design holds promise for overcoming key obstacles in solid tumor immunotherapy. We conclude by highlighting the potential of ADA1-based strategies and offering our perspective on their translation toward clinical application.

Keywords:  CAR T cells; adenosine; adenosine deaminase; inosine; metabolic reprogramming; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers18010034
Biomol Ther (Seoul). 2026 Jan 01. 34(1): 30-44

Advancing Cancer Immunotherapy: Chimeric Antigen Receptor (CAR)-T Cell Engineering through Novel Screening Methods.

Junyoung Ha, Jihye Seong.

  Cancer immunotherapy represents a paradigm-shifting achievement in oncology. Particularly, chimeric antigen receptor (CAR)-T cell therapy utilizing genetically engineered T cells has produced remarkable clinical responses in hematological malignancies. However, significant challenges still remain including limited efficacy in solid tumors and critical safety concerns. The functionality of CAR-T cells depends on their synthetic receptor, CAR, which redirects T cell specificity and enhances effector functions. Therefore, optimal CAR engineering is crucial for successful development of CAR-T cell therapy. In this review, we discuss the limitations of current CAR screening methods, which primarily assess antigen binding affinity in vitro and often fail to predict T cell function and in vivo therapeutic performance. Advanced cell-based screening platforms have been developed to overcome these limitations. We overview the principles of these CAR screening systems utilizing reporter cell lines. While most are based on the detection of antigen binding properties or CAR-T cell activation markers, we emphasize a FRET-based immunological synapse biosensor as a powerful system that directly assesses CAR activation upon antigen binding. This platform offers significant advantages in speed and scalability for predicting CAR-T cell functionality. We also discuss recent advances in CAR library screening directly in primary T cells, which provides more physiologically relevant data. Such advanced platforms are essential to accelerate the development of safe and effective CAR-T therapy for solid tumors, ultimately expanding the therapeutic potential of this transformative cancer treatment.

Keywords:  Biosensor; CAR-T cell therapy; Cancer immunotherapy; Chimeric antigen receptor; Fluorescence resonance energy transfer

DOI:  https://doi.org/10.4062/biomolther.2025.204
Res Sq. 2025 Dec 12. pii: rs.3.rs-8215051. [Epub ahead of print]

PD-1 regulates CD4+ T cell-mediated CD8+ T cell responses in the brain to balance viral control and neuroinflammation.

Aron Lukacher, Arrienne Butic, Elia Afanasiev, Samantha Spencer, Mofida Abdelmageed, Anirban Paul, Kalynn Alexander, Katelyn Ayers, Todd Schell, Matthew Lauver, Ge Jin, Samantha Borys, Laurent Brossay, Jo Anne Stratton, Vonn Walter.

Programmed cell death protein 1 (PD-1) is expressed by T cells during progressive multifocal leukoencephalopathy (PML), a life-threatening brain disease caused by the human-only JC polyomavirus. Why PD-1 blockade finds variable success in PML patients is unclear. Brain CD4+ and CD8+ T cells are PD-1high during mouse polyomavirus (MuPyV) encephalitis. Here, we show that PD-1 loss during MuPyV infection acts in a brain-autonomous manner to increase the magnitude of brain-infiltrating CD4+ and CD8+ T cells and the function of virus-specific CD8+ T cells; in concert, brain virus levels decline and neuroinflammation increases. Deletion of PD-1 in CD4+ T cells, but not CD8+ T cells, recapitulates effects of global PD-1 loss. Single-cell RNA sequencing shows that PD-1-deficient CD8+ T cells cluster as effectors while transcripts associated with proliferation and function are upregulated with loss of PD-1. Thus, CD4+ T cell-intrinsic PD-1 signaling balances antiviral defense against neural injury during polyomavirus CNS infection.

DOI: https://doi.org/10.21203/rs.3.rs-8215051/v1
JCI Insight. 2026 Jan 08. pii: e190531. [Epub ahead of print]

IL-21 enhances the cytotoxicity of intratumoral CD8+ T cells improving radiation efficacy.

Xinyang Li, Xueqi Xie, Baochao Wei, Xiaozheng Sun, Minxin Chen, Rufei Liu, Qingxu Tao, Yiheng Huang, Qian Wang, Shuangshuang Ma, Ling Wei, Rong Xiao, Zhaoyun Liu, Jinming Yu, Meng Wu, Dawei Chen.

  Radiotherapy is a critical modality in cancer treatment, not only to eradicate cancer cells but also to trigger anti-tumor immunity. Interleukin-21 (IL-21), an immunomodulatory cytokine with potential in cancer therapy, has unexplored synergy with radiotherapy. Our study, leveraging human cancer databases and tissue microarrays, identified a positive correlation between IL-21 and radiotherapy outcomes, particularly in tumor microenvironment (TME) activation. In mouse tumor models, IL-21 combined with radiation significantly enhances TME, boosting CD8+ T cell activation and function, reducing tumor burden, and extending survival. Single-cell transcriptome sequencing revealed that the combination of IL-21 and radiation increased the cytotoxicity of effector and memory CD8+ T cells and prevented their exhaustion. These effects were further validated in humanized mice, where IL-21 combined with radiation reduced A549 tumor growth and enhanced CD8+ T cell function. Post-neoadjuvant radiotherapy samples from patients with esophageal cancer showed a positive correlation between IL-21 levels and CD8+ T cell infiltration. Our findings suggest that IL-21 is a promising adjuvant to radiotherapy, potentially improving the treatment efficacy through TME enhancement. This study provides a foundation for future clinical exploration of IL-21 for enhancing radiotherapy.

Keywords:  Cancer immunotherapy; Oncology; Radiation therapy; T cells; Therapeutics

DOI:  https://doi.org/10.1172/jci.insight.190531
Front Immunol. 2025 ;16 1735479

SAA restricts T cell mediated anti-tumor immunity by limiting antigen presentation in lung cancer.

Mei Huang, Run Shi, Cong Xu, Yihan Zhang, Xiaoyue Du, Shaodi Wen, Chunbin Wang, Feng Jiang, Guoren Zhou, Xin Wang, Bo Shen.

   Background: Serum amyloid A (SAA), an acute-phase pro-inflammatory protein, is overexpressed in several cancers and is involved in shaping pro-tumor responses. We have previously reported that lung cancer stem cells secrete SAA, which contributes to tumor progression by inhibition of TH1 immunity. Here, we extended our studies to examine the mechanism of SAA mediated immunosuppression in both antigen-presenting cells (APCs) and the subsequent activation of T cells.
Methods & results: Using ex vivo co-culture systems and in vivo mice models, we found that SAA impaired dendritic cell and macrophage activation and drove macrophages toward an M2 phenotype with reduced antigen presentation. Lung cancer cells overexpressing SAA also consistently showed impaired CD8+ T cell infiltration and cytotoxicity, while SAA neutralization were efficient at enhancing CD8+ T cell activation and response to anti-tumor immunity. Mechanistically, we found that the immunosuppressive phenotype induced by SAA on APCs is mediated in part by CD36. Critically, inhibiting SAA by neutralization antibody recovered APC activity and enhanced T cell-dependent tumor control.
Conclusion: our results identify SAA as an important immunosuppressive mediator in the tumor microenvironment, implying that the SAA neutralizing antibody may be a potential target for the improvement of lung cancer immunotherapy.

Keywords:  APC; CD36; SAA; cancer immunotherapy; lung cancer

DOI:  https://doi.org/10.3389/fimmu.2025.1735479
Mol Cancer Ther. 2026 Jan 08.

TPP-45142-an Anti-HER2 T cell Engager-Designed for Selective HER2-Low Cancer Immunotherapy.

Evelyn De Tavernier, Peter S Kim, Eduardo M Bruch, Virna F Cortez-Retamozo, Lien Timmerman, Alyssa L Flynn, Wouter Van Overbeke, Fabrice Tirode, Valeria Cintra Barbosa-Lorenzi, Peter Piepenhagen, Thuvan Dinh-Le, Ernesto Luna, Aiqun Li, Ann Baker, Alexey Rak, Lily I Pao, Ana Paula B Vintém.

The standard of care for patients with HER2-positive cancers is well established, but a significant unmet need exists for patients with HER2-low tumors, who do not meet the eligibility criteria for trastuzumab, and for patients with HER2-positive tumors, who are refractory to trastuzumab treatment. Therefore, in this study, we developed a NANOBODY® domain-based HER2-targeting, T cell receptor (TCR)αβ-based T cell engager (TCE) molecule-TPP-45142; it recognizes a HER2 epitope distinct from that recognized by trastuzumab and pertuzumab and redirects T cells to kill HER2-low cancers such as breast, gastric, and gastroesophageal junction adenocarcinoma (GEJ) cancers. TPP-45142 mediated potent T cell-dependent cytotoxicity against HER2-low cancer cell lines in vitro and inhibited in vivo tumor growth of HER2-low breast cancer xenografts. TPP-45142 was highly selective toward tumor cells expressing low HER2 levels than toward normal cardiac cells and exhibited a favourable therapeutic index as per a cytokine release assay. Thus, TPP-45142, with an improved safety profile, is a promising next-generation TCE for treating challenging HER2-low cancers.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-0654
Radiat Oncol J. 2025 Dec;43(4): 165-171

Systemic immune-inflammation index prior to postoperative radiotherapy as a tool for outcome prediction in thymic epithelial tumors.

Alper Kahvecioglu, Mervenur Bay, Pervin Hurmuz, Mustafa Cengiz.

   PURPOSE: The systemic immune-inflammation index (SII) is a prognostic biomarker in various solid tumors. However, the prognostic role of SII in thymic epithelial tumors (TETs) receiving adjuvant radiotherapy (RT) has not yet been explored. This study aims to assess the prognostic role of pre-RT SII in TET patients undergoing adjuvant RT.
MATERIALS AND METHODS: A retrospective analysis was conducted on 37 patients treated with adjuvant RT for TETs between 2004 and 2023. The median adjuvant RT dose was 54 Gy (range, 50 to 70) delivered over 25-35 fractions. SII was calculated based on hemogram parameters within the two weeks preceding the start of RT, and its prognostic role was evaluated.
RESULTS: Median follow-up was 90 months (range, 12 to 230). The 5-year overall survival (OS) and disease-free survival (DFS) rates were 97.1% and 90.7%, respectively. The receiver operating characteristic analysis determined an optimal SII cut-off value of 916 for predicting recurrence (specificity, 67%; sensitivity, 71%). In univariate analysis, patients with an SII ≥916 had significantly lower 5-year OS (92.3% vs. 100%, p=0.028) and DFS (73.1% vs. 100%, p=0.011) compared to those with a SII below 916. In multivariable analysis, no variable remained statistically significant, likely due to limited events and small sample size.
CONCLUSION: Postoperative, pre-RT SII may have potential prognostic relevance in patients with TETs undergoing adjuvant RT. Elevated SII levels could be explored as a biomarker to help guide more individualized treatment and follow-up strategies; however, further studies are needed to validate these findings.

Keywords:  Inflammation; Radiotherapy; Thymic carcinoma; Thymoma

DOI:  https://doi.org/10.3857/roj.2025.00143
ACS Nano. 2026 Jan 08.

Engineering T Cells with Membrane-Anchored Nitric Oxide Scavengers for Anticancer Therapy.

Jihye Lee, Yeoul Kang, Seonwoo Kang, Hyungjin Sun, Heeyeon Yoon, Junsang Doh, Won Jong Kim.

  T cells are fundamental for orchestrating cancer-specific cytotoxic responses that are central to the success of immune-activation-related cancer therapy. However, the immunosuppressive tumor microenvironment (TME) undermines the effectiveness of T cell therapy by inducing dysfunction and promoting apoptosis of infiltrated T cells. Considering that nitric oxide (NO) is abundantly present in the immunosuppressive TME and acts as a mediator of T cell dysfunction, we aimed to modulate the NO levels within the local T cell environment to enhance the efficacy of T cell therapy. We designed membrane-fusible NO-scavenging liposomes (LipoNOX) to regulate intracellular NO accumulation in T cells within the TME. LipoNOX, which is composed of o-phenylenediamine-containing lipids and 1,2-dioleoyl-3-trimethylammonium-propane, effectively integrated into the plasma membrane and protected the T cells from NO-mediated protein modifications, including S-nitrosylation and tyrosine nitration. LipoNOX-engineered T cells (NOX-T cells) exhibited a revival of proliferation and activation in immunosuppressive TME-mimicking in vitro conditions without compromising their physiological integrity. This functionality significantly augmented the efficacy of T cell therapy in the B16-F10-OVA mouse model of tumor by increasing the population and activity of tumor-infiltrating T cells, thus providing a solid foundation for strategies targeting NO modulation in T cells.

Keywords:  T cell engineering; fusogenic liposome; membrane anchoring; nitric oxide; tumor microenvironment

DOI:  https://doi.org/10.1021/acsnano.5c06907
bioRxiv. 2025 Dec 29. pii: 2025.12.24.696419. [Epub ahead of print]

Macrophage-Dendritic Cell-T-Cell Tetrads Orchestrate Antitumor Immunity and Response to Checkpoint Blockade.

Mehdi Chaib, Muhammad Aminu, Shelley Herbrich, Mahshid Arabi, Yue Xuan, Akshay Basi, Anna Casasent, Marc D Macaluso, Kenneth H Hu, Matthew Gubin, Xi Chen, James J Mancuso, Sreyashi Basu, Sonali Jindal, Jared Burks, Stephanie Watowich, Jia Wu, James P Allison, Padmanee Sharma.

Immune checkpoint inhibitors (ICIs) elicit durable responses in only a subset of patients with solid tumors, underscoring the need to define the cellular architectures that govern effective antitumor immunity. Here we identify a spatially organized multicellular immune unit comprising macrophages, cDC1s, CD4⁺ T-cells, and CD8⁺ T-cells that emerges in response to anti-CTLA-4 or dual checkpoint blockade. We term these structures tetrads . Using multiplexed imaging and spatial transcriptomics in mouse and human tumors, we show that tetrads assemble early during immune priming, depend on the ICOS-ICOSL pathway, and are enriched for ICOS⁺ Th1-like CD4⁺ T cells and ICOSL high cDC1s. CD8⁺ T-cells within tetrads exhibit an activated, non-terminally differentiated state, while tetrad-associated macrophages display an interferon-γ-responsive program that sustains CD8⁺ T-cell function and prevents dysfunction. Functionally, ICOSL⁺ cDC1s are required for tumor eradication in vivo . In patients with bladder cancer treated with neoadjuvant dual checkpoint blockade, tetrad, but not triad or dyad formation correlates with clinical response. These findings establish tetrads as a fundamental cellular unit coordinating antitumor immunity and responsiveness to ICIs.

DOI: https://doi.org/10.64898/2025.12.24.696419
Clin Transl Oncol. 2026 Jan 06.

Conversion therapy using transarterial chemoembolization plus tislelizumab for unresectable hepatocellular carcinoma: effects on tumor necrosis and anti-tumor immune response.

Qihang Yao, Guangwen Chen, Yang Yu, Zeping Chen, Xiao An, Xueqian Xie, Qingguo Wang, Desheng Chen, Hongcheng Sun.

   PURPOSE: We analyzed the clinical efficacy and safety of conversion therapy for unresectable hepatocellular carcinoma (uHCC) using transarterial chemoembolization (TACE) plus tislelizumab and characterized its effects on the tumor and immune landscape.
METHODS: Fifty-seven patients with uHCC undergoing TACE plus tislelizumab from March 2020 to October 2024 were potentially eligible, and thirty-two patients finally enrolled. The efficacy endpoints included successful conversion rate, objective response rate (ORR), overall survival (OS), and progression-free survival (PFS). Tumor response was assessed using modified Response Evaluation Criteria in Solid Tumors (mRECIST). Treatment-related adverse events (TRAEs) were recorded according to CTCAE v5.0. Hematoxylin and eosin (HE) staining was used to evaluate tumor necrosis and lymphocyte infiltration. Immunohistochemistry (IHC) was performed to differentiate tumor immune infiltrates via a set of markers.
RESULTS: The best overall responses were 9.4% CR, 46.9% PR, 37.5% SD, and 6.3% PD, the ORR was 56.3%. Better ORR was shown in patients with AFP ≥ 400 ng/mL or tumor number < 3. The median PFS and OS was 13.9 (95% CI 2.6-25.2) and 29.2 (95% CI 13.7-44.7) months, respectively. Thirty-two patients (100%) experienced TRAEs of any grade, eight patients (25%) experienced grade 3/4 TRAEs. Fifteen patients (46.9%) with uHCC successfully converted. Notably, HE staining revealed extensive tumor necrosis and massive infiltration of lymphocytes in HCC and at the tumor-non-tumor interface in converted specimens. Further characterization by IHC revealed increased infiltration of CD8 + T and Th1 cells in the tumor of converted patients.
CONCLUSION: TACE plus tislelizumab may be a potent and safe conversion regimen for uHCC due to its ability to generate profound tumor necrosis and anti-tumor immune response.

Keywords:  Anti-tumor immune response; Conversion therapy; Tislelizumab; Transarterial chemoembolization; Unresectable hepatocellular carcinoma

DOI:  https://doi.org/10.1007/s12094-025-04159-7
Biomol Ther (Seoul). 2026 Jan 01. 34(1): 124-135

Adaptive Immunity and Alzheimer's Disease: Dual Roles in Neurodegeneration and Neuroprotection with Therapeutic Implications.

You Min Ahn, Min-Kyoo Shin.

  Alzheimer's disease (AD) is a progressive neurodegenerative disorder defined by amyloid-β (Aβ) plaques, tau hyperphosphorylation, and neuroinflammation. Although earlier work emphasized brain-resident glia (microglia and astrocytes), recent studies highlight adaptive immune cells, particularly T and B lymphocytes, as modulators of AD pathology. This review synthesizes animal and human findings from 2022-2025 to provide updated insights into the multifaceted roles and therapeutic potential of adaptive immunity in AD. Infiltration of peripheral T and B cells into the brain parenchyma links peripheral immunity to central nervous system (CNS) pathology. Both infiltrating lymphocytes and resident glia show context-dependent dual effects, either exacerbating neurodegeneration or promoting neuroprotection. Therapeutic strategies under active investigation include modulation of CD4+ T cell differentiation, adoptive transfer of regulatory T cells, and next-generation active vaccines for AD. Overall, selective modulation of discrete immune subsets may enable adaptive-immunity-based treatments, a complex yet promising avenue for AD therapy.

Keywords:  Adaptive immunity; Alzheimer’s disease; B lymphocyte; Immunotherapy; T lymphocyte

DOI:  https://doi.org/10.4062/biomolther.2025.199
Clin Transl Oncol. 2026 Jan 03.

Loss of ARID1A expression is associated with worse survival and reduced tumor infiltrating lymphocytes in advanced clear cell renal cell carcinoma.

Mohamed Ashraf Mansour, Reshmi Patel, Faiz Mumtaz, Ekaterini Boleti, Axel Bex, Maxine Gia Binh Tran, Soha El-Sheikh.

   BACKGROUND: Patients with metastatic clear cell renal cell carcinoma (ccRCC) are often treated with immunotherapy (ICI), with no definitive biomarkers of response. ARID1A is mutated among ICI responders in several cancer types, including ccRCC. Immunohistochemistry (IHC) is a widely available method of detecting ARID1A protein levels. Assessment of tumor infiltrating immune cells (TILs) also has been linked to ICI response in some studies.
PATIENTS AND METHODS: We explored the expression of ARID1A protein using IHC (manual and QuPath) in a cohort of 29 patients with metastatic ccRCC who had undergone cytoreductive nephrectomy (CRN). We correlated ARID1A expression with clinicopathological data, survival, and TILs. We corroborated our IHC results in 488 cases from the TCGA-KIRC dataset, and utilized immune deconvolution platforms to define changes in TILs in relation to ARID1A in TCGA-KIRC and an ICI-therapy validation cohort.
RESULTS: Low ARID1A protein expression is associated with large tumor size, lymphovascular invasion, high stage, low TILS, and worse overall survival. Low ARID1A mRNA in TCGA-KIRC similarly had significantly worse survival and were immune cold histologically and in ESTIMATE immune score. xCell showed significant enrichment of Th1, Th2, myeloid dendritic cells, macrophages, and T NK cells in low ARID1A mRNA ccRCC with elevation of Tregs in tumors that have high ARID1A.
CONCLUSION: Low ARID1A expression (protein and mRNA) is a marker of poor prognosis in ccRCC, and is associated with shorter survival and reduced TILs, but immune cells linked to ICI response are increased offering an immune advantage to ARID1ALow patients who receive ICI therapy. ARID1A IHC provides comparable results to bulk mRNA analysis, suggesting that it can be reliably used to explore ARID1A as a potential ICI biomarker in ccRCC.

Keywords:  ARID1A; Immunohistochemistry; Immunotherapy; Renal cell carcinoma; Tumor infiltrating lymphocytes

DOI:  https://doi.org/10.1007/s12094-025-04166-8
J Hepatocell Carcinoma. 2025 ;12 3077-3090

Prognostic Role of Mitotic Index in Hepatocellular Carcinoma: Potential Clinical Implications for Very Early Stage Disease.

Sangjoon Choi, Yoon Ah Cho, Sujin Park, Hyun Hee Koh, Boram Park, Kyunga Kim, Ju Dong Yang, Sang Yun Ha.

   Background: Surgical resection and ablation therapy are both primary treatment options for very early stage hepatocellular carcinoma (HCC). Accurate risk stratification is important, since patients at higher risk of recurrence may derive greater benefit from curative resection than from ablation. We investigated whether the mitotic index is associated with early recurrence in HCC and may serve as a prognostic marker to refine risk assessment in very early stage disease.
Methods: The number of mitoses was counted in representative tumor slides from 942 cases of surgically resected HCC from Samsung Medical Center. A high mitotic index was defined as more than eight mitoses in 10 high-power fields. The relationship between mitotic index, clinicopathological characteristics, and prognosis were analyzed. External validation was performed using 112 HCC cases obtained from Hallym University Sacred Heart Hospital.
Results: High mitotic index was identified in 296 patients and was significantly associated with aggressive clinicopathological features including higher Edmondson grade, advanced American Joint Committee on Cancer T stage, and early tumor recurrence. Patients with a high mitotic index displayed a significantly shorter early recurrence-free survival (e-RFS). In subgroup analysis of patients with very early stage, the high mitotic index group showed unfavorable influences on e-RFS.
Conclusion: High mitotic index is a significant predictor of early recurrence in HCC patients and may provide useful prognostic information in very early stage disease. While its direct role in guiding primary treatment selection is limited, the mitotic index could contribute to risk stratification and postoperative management strategies.

Keywords:  hepatocellular carcinoma; mitosis; mitotic index; prognosis; recurrence

DOI:  https://doi.org/10.2147/JHC.S541099
Nat Commun. 2026 Jan 08.

TIGIT disruption rescues the antitumor activity of low avidity TCR-engineered T cells by increasing TCR signal strength.

Martina Spiga, Alessia Potenza, Zulma Magnani, Stefano Beretta, Barbara Camisa, Laura Conte, Alessia Airaghi, Neda Mohammadi, Laura Perani, Claudio Doglioni, Maurilio Ponzoni, Francesca Sanvito, Chiara Balestrieri, Lucia Sergi Sergi, Oronza A Botrugno, Giulio Giovannoni, Giovanni Tonon, Danilo Abbati, Chiara Iozzi, Maximilian Reichert, Hana Algul, Arianna Pocaterra, Martina Fiumara, Samuele Ferrari, Alessia Ugolini, Alice Grometto, Giulia Di Lullo, Giovanni Sitia, Giulio Belfiori, Maria Pia Protti, Renato Ostuni, Anna Mondino, Michele Reni, Stefano Crippa, Massimo Falconi, Luigi Naldini, Eliana Ruggiero, Chiara Bonini.

T-cell avidity is a major determinant of Adoptive T cell therapy (ACT) efficacy for cancer treatment. However, high-avidity tumor-specific T cells can rarely be isolated from cancer patients, highlighting the need for strategies to enhance the cytotoxic capacity of low-avidity cells. Here, we rescue the anti-tumor functions of low-avidity T cells against pancreatic ductal adenocarcinoma (PDAC) by knocking-out TIGIT, a key inhibitory molecule expressed on exhausted CD8+ T cells infiltrating gastrointestinal tumors. We uncover that TIGIT disruption by base editing boosts the intracellular signal transduction derived from a weak T cell receptor (TCR) engagement enforcing cytoskeletal rearrangements, thus increasing T cell avidity and stabilizing the immunological synapse. Accordingly, TIGIT disruption enables low-avidity T cells to exert robust degranulation, comparable to that of high-avidity T cells, and potent and durable anti-tumor capacity in vivo in male mice. These results highlight TIGIT knockout as a potential strategy to enhance low-avidity T cell function and broaden the repertoire of TCR engineered T cells in the treatment of pancreatic cancer and other solid malignancies.

DOI: https://doi.org/10.1038/s41467-025-67263-w
Glob Health Med. 2025 Dec 31. 7(6): 416-422

Improved prognostic predictability of the latest Japanese TNM Classification in patients undergoing resection for distal cholangiocarcinoma.

Kohei Nishio, Sayaka Tanaka, Ryota Tanaka, Shigeaki Kurihara, Sadaaki Nishimura, Jun Tauchi, Masahiko Kinoshita, Hiroji Shinkawa, Kenjiro Kimura, Takeaki Ishizawa.

  In March 2021, the Japanese TNM Classification for Cancer of the Biliary Tract (JCCB) was revised. This study aimed to validate the 7th edition of JCCB based on long-term outcomes after resection for distal cholangiocarcinoma (DCC). We retrospectively reviewed 107 patients with resected DCC without distant metastasis between 2007 and 2019. Survival curves according to TNM factors were compared between the 6th and 7th editions. The 5-year overall survival (OS) and recurrence-free survival rate (RFS) were 43.4% and 35.5%, respectively. Significant differences in OS were observed between T categories in the 7th edition (T1 vs. T2, p = 0.049; T2 vs. T3, p = 0.027), but not in the 6th. The N classification also showed better prognostic discrimination in both editions, with more refined stratification in the 7th. Stage grouping in the 6th edition failed to show significant OS differences, while the 7th edition demonstrated clear stratification (e.g., Stage I vs. IIA, p = 0.0274; StageⅡA vs. StageⅡB, p = 0.0043; StageⅡB vs. StageⅢA, p = 0.0108). These findings indicate that the revised T and N classifications in the 7th edition more accurately reflect postoperative prognosis for resected DCC. Overall, our results support the clinical validity and improved prognostic utility of the 7th edition compared with the 6th edition.

Keywords:  depth of invasion; invasive tumor thickness; overall survival

DOI:  https://doi.org/10.35772/ghm.2025.01106
Eur J Surg Oncol. 2026 Jan 02. pii: S0748-7983(26)00003-X. [Epub ahead of print]52(2): 111384

Development and validation of the APTNM staging system: Integration of serum biomarkers with TNM classification for enhanced prognostic stratification following hepatectomy for hepatocellular carcinoma.

Eastern HepatoBiliary Alliance (EHBA) group

   BACKGROUND: Current tumour-node-metastasis (TNM) staging for hepatocellular carcinoma (HCC) relies primarily on anatomical factors without incorporating tumour biological characteristics, limiting prognostic precision. This study aimed to develop and validate a novel staging system integrating serum biomarkers alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II) with conventional TNM classification to enhance prognostic stratification following hepatectomy.
METHODS: This multicentre cohort study included patients undergoing curative hepatectomy for HCC at six hospitals in China. The APTNM staging system was constructed by combining preoperative AFP (≥200 μg/L = 1 point), PIVKA-II (≥400 mAU/mL = 1 point), and AJCC 8th edition TNM stage (stages I-III = 1-3 points). Patients were classified as APTNM stage I (1 point), stage II (2-3 points), or stage III (4-5 points). Prognostic performance was evaluated using Kaplan-Meier analysis, multivariate Cox-regression, net reclassification improvement (NRI), and time-dependent receiver operating characteristic (ROC) curves.
RESULTS: Among 660 HCC patients, the APTNM staging system demonstrated clear stratification for 5-year overall survival (OS) [stage I (n = 195), 47.7 %; stage II (n = 316), 28.1 %; stage III (n = 149), 15.3 %; P < 0.001] and recurrence-free survival (RFS) (stage I, 29.4 %; stage II, 12.7 %; stage III, 0.0 %; P < 0.001). Multivariate analysis confirmed APTNM staging as an independent predictor of both OS (stage II: HR 1.592, 95 % CI 1.209-2.096; stage III: HR 2.314, 1.668-3.211; both P < 0.001) and RFS (stage II: 1.556, 1.230-1.969; stage III: 2.159, 1.623-2.872; both P < 0.001). Time-dependent NRI values ranged from 0.20 to 0.26 for OS and 0.18-0.31 for RFS across 5-year follow-up, demonstrating substantial improvement over conventional TNM staging. Time-dependent ROC analysis consistently showed superior performance for the APTNM staging.
CONCLUSIONS: The APTNM staging system successfully integrates tumour biomarkers with anatomical factors, providing significantly enhanced prognostic stratification compared with conventional TNM staging. This biologically informed approach may facilitate more precise risk stratification and guide individualised postoperative surveillance and adjuvant therapy decisions for patients with HCC.

Keywords:  Alpha-fetoprotein; Hepatocellular carcinoma; Protein induced by vitamin K absence or antagonist-II; Recurrence; Staging system; Survival; Tumor-node-metastasis

DOI:  https://doi.org/10.1016/j.ejso.2026.111384
Oncoimmunology. 2026 Dec 31. 15(1): 2611615

The LXRβ/NF-κB axis reprograms CAR-T cells to resist exhaustion in the tumor microenvironment.

Minji Lim, Sang-Eun Jung, Choong-Hyun Koh, Hyungwoo Jeong, Youngchae Moon, Hyungseok Seo.

  Liver X receptor β (LXRβ) is a key transcription factor involved in lipid metabolism and immune regulation, yet its functional role in tumor-infiltrating T cells remains largely unresolved. While LXRβ has been shown to suppress NF-κB target gene expression, the mechanistic interaction between LXRβ and NF-κB signaling in the tumor microenvironment (TME) has not been fully established. In this study, we identify LXRβ as a critical regulator of CAR-T cell differentiation, the metabolic state, and effector function within solid tumors. LXRβ overexpression altered the transcriptional and phenotypic landscape of CAR-T cells, including the modulation of stem-like TCF1⁺ populations, proliferative capacity (Ki-67), and cytokine production (IFNγ, TNFα). Through genetic perturbation of NF-κB components, particularly RelB, we further demonstrate that disrupting non-canonical NF-κB signaling enhances CAR-T cell cytotoxicity and attenuates exhaustion-related features such as TOX upregulation. Notably, combined targeting of LXRβ and RelB produced additive and, in some settings, synergistic benefits, improving metabolic fitness, reducing terminal exhaustion, and augmenting anti-tumor activity in vivo. Together, these findings define an LXRβ-NF-κB regulatory axis that shapes CAR-T cell fate and function in the TME and highlight this pathway as a promising target for improving CAR-T cell-based therapies against solid tumors.

Keywords:  Chimeric Antigen Receptor T-cell (CAR-T); LXRβ; NF-κB; cancer immunotherapy

DOI:  https://doi.org/10.1080/2162402X.2025.2611615
Sci Rep. 2026 Jan 05.

Brain-infiltrating CD8 T cells retain functional activity to protect against acute Zika virus infection.

Jaehui Kim, Wooseong Lee, Do Yeon Kim, Keun Bon Ku, Young-Chan Kwon, Kyun-Do Kim, Chonsaeng Kim, Dae-Gyun Ahn, Seong-Jun Kim, Sungjun Park.

  Zika virus (ZIKV) infection can cause severe neurological complications, yet the role of CD8+ T cells in controlling viral pathogenesis in the brain remains unclear. Using Ifnar1-/- mice, which lack type I interferon signaling, we demonstrate that ZIKV infection triggers significant infiltration of CD8+ T cells into the brain, accompanied by neurological defects. ZIKV-experienced CD8+ T cells exhibit enhanced cytotoxic potential, and adoptive transfer of these cells improves survival. In contrast, blocking their infiltration exacerbates brain inflammatory and injury-associated signatures, highlighting their protective contribution. Furthermore, PD-1 blockade worsens ZIKV pathology, suggesting that PD-1 expression reflects an activated rather than exhausted state. These findings underscore an important role of infiltrating CD8+ T cells in reducing ZIKV-induced CNS inflammation and suggest that modulating their response could serve as a potential therapeutic strategy for ZIKV-associated neurological disease.

Keywords:   Ifnar1 −/− mouse model; Acute infection; CD8+ T cells; Cytotoxicity; Immune cell infiltration; Neuroinflammation; T cell trafficking; Zika virus (ZIKV)

DOI:  https://doi.org/10.1038/s41598-026-35079-3
Pharm Res. 2026 Jan 08.

Design, Development, and Characterization of a Tannic Acid-loaded Transfersomal Gel for Psoriatic Skin.

Mohammad Shaif, Poonam Kushwaha, Shazia Usmani, Supriya Pandey.

   BACKGROUND: Psoriasis is a chronic immune-mediated skin disorder marked by excessive keratinocyte proliferation, inflammation, and impaired barrier function, all of which limit effective topical drug delivery.
OBJECTIVES: To develop and optimize a tannic acid-loaded transfersomal gel to improve transdermal delivery, skin deposition, and therapeutic efficacy in psoriatic skin.
METHODS: Transfersomes were prepared using the thin-film hydration method and optimized through a Box-Behnken design evaluating surfactant type, total lipid content, and phospholipid-to-surfactant ratio. The optimized vesicles were analyzed for particle size, PDI, zeta potential, and entrapment efficiency. Transfersomes were incorporated into a carbopol gel, and evaluated through rheological testing, in vitro release, ex vivo permeation studies, and in vivo antipsoriatic activity using an imiquimod-induced psoriasis mouse model.
RESULTS: The optimized Span-80-based formulation showed a particle size of 205 nm, PDI 0.209, zeta potential -26.0 mV, and 84% entrapment efficiency. Gel incorporation provided suitable rheology and sustained release (63.7% over 24 h). Ex vivo studies revealed a flux of 4.99 μg/cm2/hr, a 2.74-fold improvement over conventional gel. In vivo, the transfersomal gel significantly reduced PASI scores from 10.8 ± 0.33 (disease control) to 4.5 ± 0.24. Histopathology confirmed decreased epidermal hyperplasia and inflammation.
CONCLUSIONS: The combination of ultradeformable transfersomes with tannic acid produced enhanced permeation, sustained release, and significant antipsoriatic effects. This optimized transfersomal gel demonstrates strong potential as an effective topical therapy for psoriasis.

Keywords:  nanocarrier gel; psoriasis; tannic acid; transdermal delivery; transfersomes

DOI:  https://doi.org/10.1007/s11095-025-04011-1
J Gastric Cancer. 2026 Jan;26(1): 127-145

CLDN18.2 in Gastric Cancer: Current Therapeutic Landscape and Future Perspectives.

Fei Zhang, Ukyo Okazaki, Izuma Nakayama, Kohei Shitara.

  Claudin 18.2 (CLDN18.2), a tight junction protein selectively expressed in normal gastric epithelium and widely retained during carcinogenesis, has emerged as a promising therapeutic target for advanced gastric cancer (AGC). SPOTLIGHT and GLOW trials evaluated the anti-CLDN18.2 monoclonal antibody (mAb) zolbetuximab in combination with first-line chemotherapy, and established CLDN18.2 as a therapeutic target, initiating a paradigm shift toward a biomarker-driven treatment approach in AGC. In addition, from zolbetuximab to a diverse pipeline of promising high-affinity mAbs, bispecific antibodies, antibody-drug conjugates and chimeric antigen receptor T cells, this target has established a new and highly effective therapeutic avenue for CLDN18.2-expressing AGC. Therefore, as research progresses, CLDN18.2-targeted therapy is poised to become a cornerstone of treatment across multiple disease stages and cancer types. This review describes the biological role of CLDN18.2 in normal gastric epithelium and gastric carcinogenesis and summarizes the current therapeutic landscape and future perspectives targeting CLDN18.2 in AGC.

Keywords:  Biomarker; Claudins; Gastric cancer; Targeted therapy

DOI:  https://doi.org/10.5230/jgc.2026.26.e10