bims-spamet 2026-06-21 papers

Eur J Immunol. 2026 Jun;56(6): e70205

T Cell Exhaustion as a Regulated Differentiation Programme.

T cell exhaustion is now recognised as a structured, antigen-driven differentiation programme rather than a state of cellular fatigue. Under sustained antigen exposure, CD8+ T cells progress through distinct, hierarchically organised differentiation states, initiated by progenitor exhausted cells (TPEX), which retain self-renewal, multipotency, and responsiveness to immune checkpoint blockade. Continued stimulation drives differentiation into intermediate (TEXint) and terminally exhausted (TEX term) states, with TEXint retaining greater effector capacity than TEXterm despite both exhibiting restraint relative to functional effector T cells, alongside increasingly consolidated epigenetic architecture. Rather than reflecting immunological failure, exhaustion preserves long-term antigen surveillance while limiting tissue damage. Convergence between exhaustion-associated transcriptional modules and tissue-resident memory (TRM) programmes highlights shared mechanisms of adaptation to restrictive microenvironments. Yet TRM and TEX arise in distinct contexts and are not interchangeable. Recognising exhaustion as a context-dependent differentiation process reframes therapeutic strategies, in line with current evidence indicating that immune checkpoint blockade primarily acts by expanding and redirecting the TPEX pool rather than reversing terminal exhaustion. This framework integrates insights from chronic infection, tumour immunology, and tissue adaptation.

DOI: https://doi.org/10.1002/eji.70205

iScience. 2026 Jun 19. 29(6): 116253

The competition of amino acid among tumors, tumor-associated macrophages and T cells based on metabolic reprogramming.

Chenyang Xianyu, Yuxiao Song, Ci Zhao, Qian Min, Zhixu Wang, Mingbo Zhang, Bicheng Zhang.

Amino acids are important nutrients in the process of tumor proliferation. Dysregulated amino acid metabolism profoundly influences tumor growth and immune cell function. Within the tumor microenvironment (TME), metabolic reprogramming of amino acids modulates the polarization of tumor-associated macrophages (TAMs) and the differentiation of T cells, processes intimately linked to tumor immune evasion. Meanwhile, metabolic reprogramming leads to amino acid competition between tumor cells and immune cells, particularly TAMs and T cells. To meet their own amino acid needs, tumors carry out a series of optimized metabolic strategies by expressing specific enzymes, cytokines, and amino acid transporters, and so forth promoting the formation of an immunosuppressive microenvironment and hindering anti-tumor immunity. Notably, this metabolic competition may exhibit spatial heterogeneity and temporal dynamics. Given the central role of amino acid metabolism in tumor progression and immune evasion, targeting key metabolic pathways represents a promising therapeutic strategy for cancer treatment.

Keywords: Cancer; Cancer systems biology; Human metabolism; Immune response

DOI: https://doi.org/10.1016/j.isci.2026.116253

Front Immunol. 2026 ;17 1847986

The trinity of T cell engagement: navigating the molecular and clinical landscape of CAR-T, TILs, and TCEs in the war against cancer.

Qiang Yang, Shaobin Wang, Fanlin Liu, Yongli Yu, Hai Zhao.

The advent of cancer immunotherapy has fundamentally restructured the oncological paradigm, moving away from agents that directly target tumor cell kinetics toward strategies that empower the host immune system to recognize and eliminate malignancy. Central to this revolution is the cytotoxic T lymphocyte (CTL), now harnessed as a potent "living drug" through engineered and naturally selected modalities. This review provides a critical, in-depth examination of the three dominant pillars of T cell-driven therapies: Chimeric Antigen Receptor T-cell (CAR-T) therapy, Tumor-Infiltrating Lymphocyte (TIL) therapy, and T Cell Engagers (TCEs). We dismantle the molecular mechanisms defining each approach, contrasting the synthetic, major histocompatibility complex (MHC)-independent signaling of CAR-T cells with the diverse, MHC-restricted TCR repertoire of TILs, and the transient, pharmacologic bridging provided by bispecific TCEs. While CAR-T therapy has achieved historic success in hematologic malignancies, its translation to solid tumors is severely compromised by the hostile tumor microenvironment (TME), characterized by metabolic insulation, physical exclusion, and profound immunosuppression. Conversely, TIL therapy offers a polyclonal strategy tailored for solid tumors but is hindered by complex biomanufacturing logistics and variable tumor immunogenicity. TCEs promise off-the-shelf accessibility but face challenges regarding persistence and on-target/off-tumor toxicity. Beyond clinical outcomes, we explore the pathophysiological underpinnings of resistance, including antigen escape mechanisms and T cell exhaustion programs. Finally, we posit that the future of curative regimens lies in rational combinatorial strategies-integrating advanced genetic engineering, metabolic reprogramming, and TME-modulating agents like oncolytic viruses-to overcome the multifaceted defenses of solid tumors.

Keywords: CAR T-cells; adoptive cell therapy; antigen escape; bispecific T cell engagers; immunosuppression; synthetic biology; tumor microenvironment; tumor-infiltrating lymphocytes (TILs)

DOI: https://doi.org/10.3389/fimmu.2026.1847986

J Immunol. 2026 Jun 07. pii: vkag120. [Epub ahead of print]215(6):

Mitochondrial potential reflects T cell fitness and function during cancer immunotherapy.

Paul L Lindau, Alex V Nesta, Caroline E Roe, Madelyn D Landis, Zaid Hatem, Allison E Sewell, Allison K Blount, Jackie E Bader, Reddy Anupama, W Kimryn Rathmell, Jonathan M Irish, Jeffrey C Rathmell, Kathryn E Beckermann.

Checkpoint inhibitors have transformed cancer treatment, yet predicting responses remains challenging. Mitochondrial quality decreases in tumor infiltrating lymphocytes and correlates with impaired antitumor immunity in animal models. Mitochondrial membrane potential (MMP) increases with T cell activation and may also indicate cellular dysfunction. Here, we assessed the MMP of tumor-associated T cells as an indicator of cell phenotypes and immunotherapy responses in non-small cell lung carcinoma and clear cell renal cell carcinoma patients. Primary tumors were collected followed by analysis of peripheral blood mononuclear cells prior to and after 3 wk on treatment with immune checkpoint inhibitors (ICIs). Peripheral blood mononuclear T cells were analyzed for MMP using tetramethylrhodamine ethyl ester (TMRE) and sorted into high and low populations. TCRβ and single-cell RNA sequencing of primary tumors identified and characterized peripheral blood T cell clones associated with the tumor microenvironment. As anticipated, ICI therapy increased the frequency of effector T cells in patients who experienced clinical benefit. TMREhigh peripheral blood T cells with tumor-matching TCRβ sequences had elevated oxidative phosphorylation gene signatures. Gene signatures of stress and exhaustion, such as Tigit and Cmc1, were also elevated in the TMREhigh CD8 T cell populations, while gene expression patterns in TMRElow cells suggested mitochondrial fitness and cell longevity. Importantly, clinical benefit from ICIs was negatively correlated with the TMREhigh CD8 T cell gene expression signature. These findings highlight a T cell population characterized by elevated MMP that correlates with exhaustion-like transcriptional states and poor response to immunotherapy.

Keywords: T cells; checkpoint inhibitor; kidney cancer; lung cancer; metabolism; mitochondria

DOI: https://doi.org/10.1093/jimmun/vkag120

iScience. 2026 Jul 17. 29(7): 116349

Integrative spatial multi-omics reveals the tumor ecosystem: From mechanistic insights to therapeutic strategies.

Wenqiao Chang, Wen Zhang, Kening Li, Ping Huang.

Tumor heterogeneity and complex microenvironment interactions drive malignant progression and therapeutic resistance. Traditional omics technologies struggle to capture this complexity due to the loss of spatial molecular context. Spatial multi-omics technologies enable the simultaneous in situ analysis of gene expression, metabolic activity, and protein function within tissue, thereby transforming cancer research. This review systematically discusses the principles and applications of spatial transcriptomics, spatial metabolomics, spatial proteomics, and their integration. These approaches have revealed spatially driving mechanisms, such as the niche at the invasive front, dynamic evolution of the immune microenvironment, and cell-cell communication networks in metastatic spread. We also highlight their potential to promote precise tumor treatment including guiding patient stratification, optimizing treatment regimens, and overcoming drug resistance. Finally, we discuss the current challenges and future development directions. This study aims to clarify how spatial multi-omics deepens the understanding of tumor biology and accelerates clinical translation through multi-dimensional information integration.

Keywords: Cancer; Microenvironment; Omics

DOI: https://doi.org/10.1016/j.isci.2026.116349