bims-spamet 2026-08-23 papers

bioRxiv. 2026 Jul 28. pii: 2026.07.25.740730. [Epub ahead of print]

Voluntary exercise during weight loss attenuates adipose CD8+ T cell exhaustion that persists after weight regain.

Okechukwu Kingsley Oforka, Emily C LaVoy, Matthew A Cottam, Munira Kapadia, Emily Nguyen, Caroline Hegemann, Alyssa H Hasty, Nathan C Winn, Heather L Caslin.

Background: Weight gain and loss induce adipose CD8+ T cell exhaustion, which persists and may worsen glucose tolerance following weight regain. Because exercise can reduce T cell exhaustion in the blood, we hypothesized that exercise during weight loss would attenuate adipose CD8+ T cell exhaustion and glucose tolerance following weight regain.
Methods: Male C57Bl/6J mice were fed low-fat or high-fat diets over 8 to 9-week cycles to generate lean, obese, weight loss, or weight cycled groups. Additional weight loss and weight cycled groups were provided exercise wheels during the weight loss phase.
Results: As expected, weight loss increased total and exhausted CD8+ T cells by flow cytometry. Mice that ran the most during weight loss had the lowest proportion of exhausted CD8+ T cells. Notably, exercise reduced the proportion of exhausted CD8+ T cells even after the cessation of exercise and weight regain in all mice. However, exercise did not improve glucose tolerance or macrophage inflammation following weight regain. Moreover, exercise did not affect the induction of innate immune memory in adipose macrophages following weight loss.
Conclusion: The addition of exercise to a weight loss intervention remarkably reduced exhausted CD8+ T cells in the adipose tissue even after the cessation of exercise and weight regain. While exercise did not affect macrophage inflammation or glucose tolerance following weight regain, these results illuminate new questions about the persistence and mechanisms by which exercise reduces tissue CD8+T cell exhaustion and the direct role of macrophages in modulating glucose tolerance with weight cycling.

DOI: https://doi.org/10.64898/2026.07.25.740730

J Clin Invest. 2026 Aug 17. pii: e207550. [Epub ahead of print]136(16):

Radiotherapy and immunotherapy in cancer treatment: mechanisms of clinical synergy.

Lu Lu, Liufu Deng.

Synergizing radiotherapy (RT) with immune checkpoint inhibitors has emerged as a promising strategy for solid tumors. RT acts as a potent immunomodulator, capable of functioning as an in situ vaccine through the induction of immunogenic cell death and activation of innate immune sensing, thereby promoting DC maturation and CD8+ T cell responses. However, RT also triggers counter-regulatory immunosuppression, including PD-L1 upregulation and the recruitment of suppressive cells, providing the biological rationale for synergy. Here, we systematically review advances in radioimmunotherapy, covering immunomodulatory mechanisms, clinical optimization of dose and sequencing, and the emerging role of artificial intelligence (AI) in guiding treatment paradigms. We adopt a spatial interaction-centric perspective to synthesize current knowledge on how RT governs the DC/CD8+ T cell interaction axis across the tumor microenvironment and tumor-draining lymph nodes, aiming to chart a rational course from empirical combination toward personalized, precision radioimmunotherapy. Furthermore, we explore how AI-driven analysis of radiomics and multiomics data is being applied to predict responders and personalize treatment planning.

DOI: https://doi.org/10.1172/JCI207550

bioRxiv. 2026 Jul 31. pii: 2026.07.30.741857. [Epub ahead of print]

Tumor-hepatocyte crosstalk drives a hepatic lactate-TGF-β axis of CD8 + T cell exhaustion and immunotherapy resistance in small-cell lung cancer liver metastases.

Amira Kazi, Yingying Cao, Chirayu Mohindroo, Abhinav Joshi, Yang Zhang, Yue Huang, Chiori Tabe, Brett Schroeder, Thorkell Andersson, Ajit Kumar Sharma, Anish Thomas.

Purpose: Liver metastases confer poor outcomes and attenuate the benefit of immunotherapy across solid tumors. This study investigated how the hepatic metastatic niche promotes CD8⁺ T cell dysfunction and immunotherapy resistance in small-cell lung cancer (SCLC).
Experimental Design: Clinical outcomes and tumor gene expression were integrated with multi-region single-cell RNA sequencing of T cells from rapid-autopsy SCLC metastases, together with spatial transcriptomics. SCLC-hepatocyte conditioned-media models were combined with stable-isotope tracing, mass spectrometry, functional and metabolic assays, and ChIP-qPCR to define mechanisms of CD8⁺ T cell suppression.
Results: Liver metastases were associated with inferior survival and reduced benefit from immune checkpoint blockade. Multi-region single-cell analysis showed that CD8⁺ T cells from liver metastases exhibited an exhaustion-associated state enriched for hypoxia, lactate, and TGF-β programs. SCLC-hepatocyte crosstalk generated a lactate- and TGF-β-rich microenvironment that reduced CD8⁺ T cell effector function, proximal T cell receptor signaling, glycolytic fitness, viability, and proliferation. Stable-isotope tracing demonstrated transfer and accumulation of co-culture-derived lactate in recipient CD8⁺ T cells, with limited entry into downstream pyruvate-linked pathways. Lactate accumulation was accompanied by increased H3K18 lactylation at the PDCD1 , LAG3 , and TGFB1 regulatory loci. In parallel, SCLC-hepatocyte crosstalk increased paracrine TGF-β and activated canonical SMAD2 signaling in CD8⁺ T cells. TGF-β receptor inhibition restored CD8⁺ T cell proliferation. In the phase III IMpower133 cohort, a combined lactate-TGF-β transcriptional program was associated with inferior survival, most strongly in patients with liver metastases.
Conclusions: Tumor-hepatocyte crosstalk generates convergent lactate and TGF-β signals that drive CD8⁺ T cell dysfunction in liver metastases. This hepatic immune-metabolic circuit provides a potential mechanism for immunotherapy resistance and supports therapeutic strategies targeting TGF-β signaling in liver-metastatic SCLC.
Translational Relevance: Patients with SCLC liver metastases have poor outcomes and derive limited benefit from immune checkpoint blockade, but actionable mechanisms of hepatic immune resistance remain undefined. We identify an immune-metabolic circuit in which SCLC-hepatocyte crosstalk generate lactate and TGF-β signals that converge on CD8⁺ T cells. Stable-isotope tracing demonstrates the transfer and accumulation of tumor-hepatocyte-derived lactate in recipient T cells, which causes H3K18 lactylation at exhaustion- and TGFB1-associated loci. In parallel, paracrine TGF-β activates canonical SMAD signaling and reinforces proliferative dysfunction. TGF-β receptor inhibition restores CD8⁺ T cell proliferation. In the phase III IMpower133 cohort, a combined lactate-TGF-β program is associated with inferior survival, particularly among patients with liver metastases. These findings provide a mechanistic and biomarker framework for testing TGF-β-directed strategies in liver-metastatic SCLC, a population with substantial unmet clinical need.

DOI: https://doi.org/10.64898/2026.07.30.741857

bioRxiv. 2026 Aug 07. pii: 2026.08.03.741871. [Epub ahead of print]

Resolving the immune response across clonal cancer evolution in situ with whole transcriptome profiling.

Shaocheng Wu, Mohita Mahajan, Maarten van der Linde, ChunFang Zhu, Robert B West, David van IJzendoorn, Magdalena Matusiak.

Single-cell spatial transcriptomics is now central to studying tumors in their native tissue context. Here we present the first comprehensive, independent evaluation of Atera, a new spatial whole transcriptome platform, compared against Xenium on adjacent sections of human ductal carcinoma in situ (DCIS). We show that Atera enables granular cell-state annotation and resolves rare cell populations, which we experimentally validate by multiplex immunofluorescence (IF). We further show that its transcriptome-wide coverage enables inference of copy-number alterations at single-cell resolution, allowing us to reconstruct the clonal evolution of DCIS. We orthogonally confirm the inferred copy-number alterations by whole-genome sequencing of 16 microdissected tumor regions from a consecutive tissue section. Finally, by mapping the immune microenvironment onto this clonal architecture, we demonstrate the feasibility of tracking the changes in immune response along the clonal tumor evolution in situ. Together, our results establish Atera as a validated platform for tracking clonal evolution and immune adaptation in clinical samples.

DOI: https://doi.org/10.64898/2026.08.03.741871

Int Immunopharmacol. 2026 Aug 21. pii: S1567-5769(26)01155-0. [Epub ahead of print]188 117308

Metabolic crosstalk between extracellular matrix, cancer-associated fibroblasts and tumor cells: drivers of tumor progression and therapeutic resistance.

Chenyu Wei, Haolin Sun, Jianglan Long, Xiaojia Liu, Quanfu Li, Bangwei Cao.

The tumor microenvironment (TME) is a critical regulator of cancer progression, with extracellular matrix (ECM) and cancer-associated fibroblasts (CAFs) as core components. Metabolic reprogramming is a hallmark of cancer, yet the metabolic crosstalk between ECM, CAFs and tumor cells updates rapidly and remains incompletely understood, and effective therapeutic strategies targeting this axis are lacking. This review summarizes that ECM stiffness and components remodel glucose, lipid, and amino acid metabolism in tumor cells via mechanotransduction and signaling pathways. Meanwhile, metabolic adaptations in turn drive ECM remodeling. In addition, CAFs exhibit high heterogeneity and undergo glycolytic, lipid, and amino acid metabolic reprogramming, providing metabolites to fuel tumor growth and mediate therapeutic resistance. Importantly, this metabolic rewiring profoundly reshapes the tumor immune microenvironment by promoting M2-like tumor-associated macrophage polarization, regulatory T cell expansion, and inhibiting CD8+ T cell mediated anti-tumor responses etc., thereby fostering immune evasion and therapeutic resistance. The reciprocal interactions among ECM, CAFs, metabolic reprogramming, and immunosuppression form a vicious cycle that drives tumor progression, metastasis, and drug resistance. Distinct from prior reviews that independently elaborate ECM mechanometabolism or CAF metabolic reprogramming, this review establishes a unified tripartite conceptual framework termed the ECM-CAF-Tumor Reciprocal Metabolic Cycle, integrating mechanical, metabolic, and immunological dimensions. This review clarifies the metabolic crosstalk mechanisms between ECM, CAFs and tumor cells, providing a theoretical basis for developing combinatorial therapeutic designs integrating metabolism-targeted agents, stroma-directed therapies and immunotherapy to amplify anti-tumor efficacy.

Keywords: Anti-tumor therapy; Cancer-associated fibroblasts; Extracellular matrix; Metabolic reprogramming; Tumor progression

DOI: https://doi.org/10.1016/j.intimp.2026.117308

Cell Rep. 2026 Aug 17. pii: S2211-1247(26)00922-8. [Epub ahead of print]45(8): 117844

Caloric restriction suppresses colorectal tumors and melanoma through CD8 T cells in aged mice.

Taichi Horino, Haruki Horiguchi, Daisuke Torigoe, Shinsei Yumoto, Tsuyoshi Kadomatsu, Koh Harada, Michio Sato, Toshiro Moroishi, Masaaki Iwatsuki, Yuichi Oike.

Caloric restriction (CR) has shown the potential to extend lifespan and reduce cancer risk; however, the mechanisms underlying CR-mediated tumor suppression are not fully understood. Here, we investigate age-dependent CR effects on tumor progression and anti-tumor immune responses in a murine CR model. In aged mice, CR, defined as a 30% reduction in caloric intake, significantly suppressed tumor growth in murine syngeneic models of colorectal cancer or melanoma. CR also enhanced tumor infiltration by CD8+ T cells, which when depleted limited the tumor-suppressive effects of CR in aged mice. RNA-seq analysis of intratumoral CD8+ T cells revealed that CR upregulated the expression of genes associated with T cell function. Furthermore, mechanistic studies of effects of CR on age-related changes in CD8+ T cells, and immunohistochemical analysis suggested that normalization of the vasculature in the tumor microenvironment of aged CR mice is accompanied by decreased expression of angiogenic growth factors secreted by intratumoral CD8+ T cells. Our findings overall provide insight into age-dependent tumor-suppressive effects of CR and illustrate the essential role of CD8+ T cells in CR-mediated tumor suppression.

Keywords: CP: cancer; CP: immunology; aging; caloric restriction; immune aging; tumor immunity; tumor microenvironment

DOI: https://doi.org/10.1016/j.celrep.2026.117844

Acta Neuropathol Commun. 2026 Aug 18. pii: 170. [Epub ahead of print]14(1):

Immune niches in brain tumors: glial-immune cell interactions and spatial microdomains.

Qian Guo, Sihang Shen, Zhouyuan Zhang, Meirong Shan, Bochen Pan, Xiao Yu, Yi Chen.

The immune microenvironment of brain tumors is characterized by remarkable diversity, where immune cells are not randomly distributed but are systematically organized into specific spatial microdomains. This spatial order is primarily orchestrated by glial cells, including astrocytes, microglia, and oligodendrocyte-lineage cells, which actively shape the local immune landscape by determining the position and activation states of infiltrating immune populations. To reflect the latest conceptual advances, this review first details the complex interaction networks through which glial cells directly modulate T-cell function and shape myeloid cell properties via cytokine signaling and metabolic regulation. We then examine how these active cellular communications synergize with the temporal process of tumor immunoediting and physical microenvironmental stressors (such as hypoxia) to drive the formation and physical anchoring of these immune niches. Consequently, these structurally established domains mature into functionally distinct, heavily immunosuppressive hubs that foster local T-cell exhaustion and coordinated immune escape. Because these niches are dynamically evolving ecosystems rather than static entities, they present profound architectural barriers, directly contributing to the heterogeneous and often limited responses to current immunotherapies. By integrating these spatial and temporal dynamics into a comprehensive conceptual framework, this review highlights the urgent clinical need to shift toward multidimensional, niche-disrupting therapeutic strategies, ultimately aiming to improve immunotherapy efficacy and clinical outcomes for patients with brain tumors.

Keywords: Glial–immune interactions; Glioblastoma; Immune niches; Immunosuppression; Immunotherapy; Microenvironmental stressors; Spatial transcriptomics; T cell exhaustion; Tumor microenvironment

DOI: https://doi.org/10.1186/s40478-026-02373-0