bims-spamet 2026-08-16 papers

J Immunother Cancer. 2026 Aug 04. pii: e015618. [Epub ahead of print]14(8):

TGF-β1 drives neutrophil extracellular traps formation to promote CD8+ T cell exhaustion via the ERK-c-Fos-JunB axis, mediating gastric cancer immunotherapy resistance.

Ziting Qu, Zhikun Wang, Yongtao Hu, Xiaoli Wei, Wenxi Ding, Sachiyo Nomura, Xiaoyu Guo, Hui Feng, Yiyin Zhang, Kangsheng Gu.

BACKGROUND: Resistance to anti-programmed cell death protein-1 (PD-1) treatment in gastric cancer (GC) is closely associated with an immunosuppressive tumor microenvironment. However, the role of neutrophils in resistance to anti-PD-1 therapy remains unclear.
METHODS: Single-cell RNA sequencing was performed on tumor samples from patients with advanced GC receiving anti-PD-1 therapy to identify neutrophil subsets associated with neutrophil extracellular traps (NETs). Multilevel experimental validation was conducted using multiomics analysis, flow cytometry, multiplex immunofluorescence, and in vitro co-culture. Therapeutic strategies targeting NETs and CD8+ T-cell exhaustion were evaluated in a mouse model of YTN16 tumors.
RESULTS: We identified a NETs-associated neutrophil subset enriched in patients with GC resistant to anti-PD-1 treatment. This subset was marked by CD177, and it exhibited a high potential for NETs release. Peripheral blood NETs levels and CD177+ neutrophil ratios in patients with GC act as markers for evaluating the efficacy of PD-1 inhibitors. Furthermore, transforming growth factor-β1 (TGF-β1), which was highly expressed in GC and spatially colocalized with CD177+ neutrophils, might induce neutrophils to release NETs via the Smad3-NFE2 axis. NETs promoted CD8+ T cell exhaustion by activating the MEK/ERK-c-Fos/JunB axis, as evidenced by increased PD-1/TIM3 expression and reduced interferon-gamma/tumor necrosis factor-alpha secretion. In vivo experiments confirmed that targeted inhibition of NETs formation using DNase I or TGF-β1 inhibitors significantly suppressed tumor growth and CD8+ T cell exhaustion. Notably, the MEK inhibitor trametinib reversed the immunosuppressive microenvironment associated with CD8+ T cell exhaustion and synergistically enhanced the antitumor efficacy with anti-PD-1 therapy.
CONCLUSIONS: TGF-β1 drives CD177+ neutrophils to release NETs, which induce CD8+ T cell exhaustion via the ERK-c-Fos-JunB pathway, thereby mediating resistance to anti-PD-1 treatment in GC. Furthermore, targeting NETs formation and combining trametinib with PD-1 inhibitors can significantly reverse CD8+ T cell exhaustion, exert synergistic antitumor effects, and offer a potential therapeutic strategy for overcoming resistance to anti-PD-1 therapy in GC.

Keywords: Gastric Cancer; Immune Checkpoint Inhibitor; Immunotherapy; Neutrophil; Tumor infiltrating lymphocyte - TIL

DOI: https://doi.org/10.1136/jitc-2026-015618

J Gene Med. 2026 Aug;28(8): e70105

PCAT6 Regulates IGF2BP1/PD-L1 to Promote Immune Escape in Breast Cancer.

Dingping Sun, Shanglong Sun, Jing Li, Liping Gu, Weijian Yang, Li Shang.

OBJECTIVE: This study aims to elucidate the mechanism through which prostate cancer-associated transcript 6 (PCAT6) modulates immune escape in triple-negative breast cancer (TNBC), focusing on its interaction with IGF2BP1 and PD-L1.
METHODS: We analyzed 68 paired TNBC clinical specimens and utilized TNBC cells (BT-549, MDA-MB-468) with lentivirus-mediated gene manipulation. Functional assays included cell counting kit-8, EdU incorporation, Transwell migration/invasion, and co-culture with activated CD8+ T cells. Immune function was assessed through LDH release, ELISA (IFN-γ and granzyme B), and flow cytometry. Molecular interactions were investigated via RNA immunoprecipitation, RNA pulldown, fluorescence in situ hybridization, and actinomycin D-based mRNA stability assays.
RESULTS: PCAT6 was markedly upregulated in TNBC tissues and cell lines, correlating with advanced tumor stage and lymph node metastasis. PCAT6 knockdown restrained tumor cell proliferation, migration, and invasion while downregulating PD-L1 expression. In co-culture systems, PCAT6 depletion enhanced CD8+ T cell cytotoxicity, evidenced by increased inflammatory factor secretion and elevated IFN-γ+ CD8+ T cell proportion. Mechanistically, PCAT6 interacted with IGF2BP1 in the cytoplasm and promoted IGF2BP1-mediated stabilization of PD-L1 mRNA. Rescue experiments confirmed that PCAT6 required IGF2BP1 to sustain PD-L1 expression and mRNA stability.
CONCLUSION: PCAT6 facilitates TNBC immune escape by enhancing PD-L1 mRNA stability through IGF2BP1, identifying the PCAT6/IGF2BP1/PD-L1 axis as a potential therapeutic target for breast cancer immunotherapy.

Keywords: IGF2BP1; PCAT6; PD‐L1; long noncoding RNA; triple‐negative breast cancer

DOI: https://doi.org/10.1002/jgm.70105

Proc Natl Acad Sci U S A. 2026 08 18. 123(33): e2528104123

Therapeutic remodeling of the tuberculosis granuloma with 1-methyl-D-tryptophan enhances CD8+ T cell-macrophage interactions.

Erin F McCaffrey, Alea C Delmastro, Bindu Singh, Annu Devi, Caden W Munson, Priyanka, Nadia A Golden, Shabaana A Khader, Michael Angelo, Deepak Kaushal, Smriti Mehra.

Granulomas, the hallmark of tuberculosis (TB) disease, can both restrict Mycobacterium tuberculosis (Mtb) dissemination and impede its clearance. Recent studies indicate that indoleamine 2,3-dioxygenase (IDO1), an immunosuppressive metabolic enzyme, limits infiltration of activated T cells and can contribute to TB disease progression. Treatment with 1-methyl-D-tryptophan (D-1MT), a small molecule inhibitor that restores mTOR signaling, has been shown to reduce IDO1 activity and improve immune responses in Mtb-infected rhesus macaques. Here, we investigated the impact of D-1MT treatment on TB granuloma architecture using 30-plex high-dimensional issue imaging in rhesus macaques. By spatially mapping 13 distinct cell populations, we found D-1MT treatment corresponded with significantly increased infiltration CD8+ T cells into granulomas compared to untreated controls. Notably, these CD8+ T cells expressed markers of cell proliferation and cytotoxicity. D-1MT enhanced CD8+ T cell infiltration throughout the granuloma, with particularly pronounced effects in the myeloid core, where we observed significantly enhanced spatial interactions between macrophages and CD8+ T cells, but not CD4+ T cells. Our results demonstrate that: i) effective intragranulomatous Mtb control is associated with the close spatial proximity between CD8+ T cells and macrophages, a feature less abundant in uncontrolled pulmonary TB; ii) IDO1 induction blocks CD8+ T cell infiltration and reduces T cell activation and proliferation; and iii) therapeutic strategies, including D-1MT, that improve intragranulomatous killing hold strong translational potential.

Keywords: Mycobacterium tuberculosis; granuloma; macaque; multiplexed imaging

DOI: https://doi.org/10.1073/pnas.2528104123

Front Immunol. 2026 ;17 1871598

Amino acid metabolic regulatory network in tumor immune escape: mechanistic exploration and intervention directions.

Zhaoxia Liu, Lin He, Yu Tian, Shipin Feng, Xiongtao Yang, Hui Wu, Qiaoshuang Pu, Yan Wang, Xiaoli Yuan.

Tumor immune escape is not determined solely by immune checkpoints, suppressive cytokines, or changes in immune-cell composition; it is also organized by the metabolic architecture of the tumor microenvironment. Reprogrammed amino acid metabolism contributes to this process by redistributing nutrients, generating immunoregulatory metabolites, and reshaping immune-cell states. Rather than viewing individual amino acid pathways as independent mechanisms, this review proposes a network framework in which nutrient competition, metabolite-mediated communication, and immune-state stabilization are mechanistically coupled across tumor, immune, stromal, vascular, and microbiota-associated compartments. We define four properties of this network: cross-pathway convergence on shared immune outcomes, division of metabolic labor among cell populations, spatial and temporal context dependence, and compensatory feedback that sustains immune suppression. Within this framework, we examine how tryptophan, glutamine, methionine, arginine, and emerging pathways such as asparagine regulate T-cell dysfunction, regulatory T-cell persistence, myeloid polarization, dendritic-cell impairment, and resistance to immune checkpoint blockade. We further discuss how network-level understanding may improve biomarker development and guide cell-selective, temporally optimized, and rational combination strategies. Conceptualizing amino acid metabolism as an interconnected regulatory system may better explain the context-dependent effects of metabolic interventions and support precision immunometabolic therapy.

Keywords: amino acid metabolism; immunometabolism; immunotherapy resistance; tumor immune escape; tumor microenvironment

DOI: https://doi.org/10.3389/fimmu.2026.1871598

Front Immunol. 2026 ;17 1903920

Formation and remodeling of immunological niches in solid tumors: organ-specific architectures, inflammatory parallels, and therapeutic reprogramming.

Zhuo Zhang, Yun Dong, Jinchao Li, Youling Shi, Aihua Mei, Miaoxin Fu.

Tumor immunity is increasingly understood not only through the cellular composition of the tumor microenvironment, but also through spatially organized local niches that can help determine where immune recognition is initiated, constrained, suppressed, or therapeutically restored. This review develops an organ-conditioned and evidence-graded framework for tumor immunological niches as spatially localized, interaction-dependent, functionally consequential, and dynamically remodeled units. Rather than reproducing a general taxonomy of cancer immune niches, we focus on how shared niche-forming mechanisms are implemented differently by organ-specific tissue rules. We first distinguish the niche concept from broad tumor microenvironment descriptions, immune infiltration, immune compartments, and tertiary lymphoid structures. We then propose an operational evidence hierarchy that separates spatial association, recurrent interaction, functional consequence, perturbation-based validation, and therapeutic actionability. Next, we synthesize core mechanisms of niche formation, including tumor-intrinsic signaling, stromal and extracellular-matrix scaffolding, chemokine and cytokine wiring, vascular-hypoxic-metabolic boundaries, myeloid-centered suppression, and tissue-resident immune imprinting. Brain and lung tumors are treated as two organizing paradigms: immune-restricted niche architecture in the central nervous system and inflammation-primed niche architecture in the lung. Oral, liver, and pancreatic tumors are discussed comparatively to show how mucosal-microbial, tolerogenic-metabolic, and desmoplastic immune-exclusion rules reshape shared niche mechanisms. We further separate tumor-specific evidence, inflammatory analogies, and hypothesis-generating parallels to avoid overextending chronic inflammation or fibrosis models. Finally, we examine how niche architecture produces T-cell exclusion, antigen-presentation failure, suppressive myeloid-stromal feedback, and therapeutic resistance, and how release, access, and licensing strategies may guide organ-tailored combinations when supported by adequate evidence. This review argues that tumor immunological niches may serve as meso-level analytical units linking spatial organization, organ context, evidence strength, inflammatory parallels, and therapeutic vulnerability when their evidentiary status is explicitly defined.

Keywords: brain tumors; inflammatory parallels; lung tumors; organ-specific immunity; spatial immunology; therapeutic reprogramming; tumor immunological niche; tumor microenvironment

DOI: https://doi.org/10.3389/fimmu.2026.1903920