bims-spamet 2026-09-27 papers

Front Immunol. 2026 ;17 1917606

PD-L1+ neutrophils at the invasive margin drive contact-dependent CD8+ T cell exhaustion in hepatic alveolar echinococcosis.

Dalin Shi, Chengwei Tie, Mingquan Pang, Xiaolei Xu, Zhixin Wang, Haijiu Wang, Haining Fan.

Introduction: Hepatic alveolar echinococcosis (HAE), a lethal chronic helminth infection caused by Echinococcus multilocularis, is characterized by pronounced local immune evasion and progressive CD8+ T cell exhaustion at the parasite?host invasive margin. However, the spatial cellular network and core regulatory subsets driving this localizedimmunosuppression remainpoorly understood.
Methods: We performed high-resolution spatial immune profiling of the lesion invasive margin (collagenous layer tissue, CLT) and paired distal normal liver tissues (DLT) from 12 HAE patients by integrating imaging mass cytometry, single-cell RNA sequencing, and multiplex immunofluorescence. The underlying molecular mechanism was validated via in vitro co-culture assays with or without Transwell physical separation, and the therapeutic potential was further confirmed in a delayed?treatment HAE mouse model using neutrophil depletion(anti-Ly6G) or PD-L1 blockade (anti-PD-L1).
Results: Spatial multi-omics identified a specific subset of APC-like PD-L1 neutrophils exclusively enriched at the HAE invasive margin, which showed striking spatial co-localization and frequent membrane-to-membrane contacts with PD-1 CD8 T cells. In vitro, activated CD8 Tcells potently induced PD-L1 upregulation on neutrophils; reciprocally, PD-L1 neutrophils significantly suppressed T cell effector function (downregulating GZMB, IFN-γ, and TNF-α) and upregulated exhaustion-associated transcription factors TOX and NR4A1 via a contact-dependent PD-L1/PD-1 pathway, effects largely abolished by Transwell separation. In the HAE mouse model, both neutrophil depletion and PD-L1 blockade significantly reduced parasite burden, alleviated liver inflammation and fibrosis, and restored CD8 T cell cytotoxicity; notably, neutrophil depletion achieved superior therapeutic efficacy compared with PD-L1 monotherapy.
Conclusion: Collectively, our findings demonstrate that PD-L1-expressing neutrophils at the HAE invasivefront contribute importantly to localized CD8 T cell exhaustion via direct cell-cell contact, anddisrupting this crosstalk represents a promising targeted strategy to restore host protective immunity against parasitic infection.

Keywords: CD8+ T cell exhaustion; PD-L1+ neutrophils; PD-L1/PD-1 axis; hepatic alveolar echinococcosis; spatial immune niche

DOI: https://doi.org/10.3389/fimmu.2026.1917606

Proc Natl Acad Sci U S A. 2026 Sep 29. 123(39): e2612774123

Thymic age and peripheral residence time determine antitumor competence of CD8+ T cells.

Yuanqin Yang, Yunyi Wang, Amanda Wicki, Qianpeng Li, Chunrun Qu, Brian Debo, Berna Bou Tayeh, Tingyu Wen, Hui Huang, Amir Hosseini, Vinnycius Pereira Almeida, Carol S Leung, Georg A Holländer, Benoit Van den Eynde, Yang Shi.

The developmental timing of T cell generation imprints durable functional programs, yet how this shapes antitumor immunity remains unclear. Here, we combine genetic fate mapping with functional assays to dissect how thymic age and peripheral residency regulate CD8+ T cell behavior within the same host. We find that, compared with adulthood-derived CD8+ T cells, the adolescent-derived counterparts consistently exhibit enhanced tumor infiltration, increased effector cytokine production, and superior proliferative fitness. Transcriptomic and phenotypic profiling identify a CXCR3+IL-18Rα+ subset preferentially enriched among adolescent-derived T cells that shares core virtual memory-like features and displays elevated cytotoxic potential. Mechanistically, thymic origin timing and time spent in the periphery independently regulate the abundance and activity of this subset, revealing a two-tier control comprising developmental bias and postthymic remodeling. Functionally, CXCR3+IL-18Rα+ CD8+ T cells mediate potent tumor killing and confer robust therapeutic benefit in adoptive transfer models. Together, these findings establish developmental imprinting as an important determinant of CD8+ T cell heterogeneity and identify CXCR3+IL-18Rα+ CD8+ T cells as key effectors for antitumor immunity.

Keywords: CD8+ T cells; antitumor immunity; developmental timing; fate mapping; thymus

DOI: https://doi.org/10.1073/pnas.2612774123

Cancer Commun (Lond). 2026 ;46 0045

Beyond Structure: The Dynamic Role of the Extracellular Matrix Components in Immune Evasion.

Mohsin Maqbool, Anju Surendranath, Sadaf Khursheed Baba, Tooba Jawwad, Imadeldin Elfaki, Rashid Mir, Rakesh Kumar, Shahab Uddin, Mohammad Haris, Muzafar Ahmad Macha, Ammira Al-Shabeeb Akil, Mayank Singh, Sameer Mirza, Ajaz Ahmad Bhat.

The extracellular matrix (ECM) is a dynamic and functionally active component of the tumor microenvironment that critically regulates immune cell trafficking, activation, and persistence. Rather than serving solely as a structural framework, ECM remodeling through collagen reorganization, proteoglycan-dependent chemokine sequestration, and fibroblast-driven matrix stiffening actively contributes to immune exclusion and evasion in solid tumors. This review integrates emerging mechanistic insights into how ECM composition, architecture, and mechanical properties shape spatial immune exclusion, T cell dysfunction, and immune-checkpoint regulation through mechanotransduction, metabolic reprogramming, and altered cytokine and chemokine signaling. Particular emphasis is placed on the coordinated activities of distinct ECM components and cancer-associated fibroblast subtypes in establishing spatially restricted immunosuppressive niches that limit antitumor immunity and therapeutic responsiveness. ECM-targeted therapeutic strategies are critically evaluated by integrating their mechanistic rationale, preclinical efficacy, clinical trial outcomes, and current stage of translational development. The importance of biomarker-guided patient stratification is also highlighted for identifying tumors most likely to benefit from ECM-directed interventions, particularly in combination with immune-checkpoint blockade and other immunotherapies. Finally, recent advances in spatial transcriptomics, proteomics, matrix imaging, and ECM-derived circulating biomarkers are discussed as tools to refine therapeutic targeting, monitor matrix remodeling, and predict treatment response. By conceptualizing the ECM as an active immunoregulatory network rather than a passive physical barrier, the review provides a mechanistic and translational framework for developing next-generation, ECM-informed cancer immunotherapies.

DOI: https://doi.org/10.34133/cancomm.0045

Curr Issues Mol Biol. 2026 Sep 10. pii: 926. [Epub ahead of print]48(9):

Lactylation Remodels Tumorigenesis, Immune Microenvironment, and Therapeutic Response.

Yufei Liu, Yutong Zhou, Huiwen Xue, Ruiru Xu, Yujiao Liu.

Lysine lactylation (Kla) is a lactate-driven post-translational modification that covalently links lactyl groups to lysine residues, directly coupling cellular metabolic states to gene expression regulation and protein functional remodeling. Since its first report in 2019, extensive studies have confirmed that lactylation is broadly present on histones and thousands of non-histone substrates. In the context of tumor biology, lactylation reinforces glycolysis through positive feedback loops, suppresses oxidative phosphorylation, remodels lipid and glutamine metabolism, and exerts regulatory functions in autophagy, pyroptosis, ferroptosis, and apoptosis, thereby comprehensively participating in tumor cell proliferation, metabolic adaptation, cell death resistance, and invasion and metastasis. Within the tumor microenvironment, lactylation constructs an immune evasion barrier by upregulating immune checkpoints, including programmed death-ligand 1 (PD-L1), driving tumor-associated macrophage polarization toward the M2 phenotype, inducing CD8+ T cell exhaustion, and enhancing regulatory T cell suppressive function. Strategies targeting lactate production (lactate dehydrogenase A (LDHA) inhibitors), lactate transport (monocarboxylate transporter (MCT) inhibitors), and the lactylation enzymatic machinery (p300/CBP inhibitors, histone deacetylase (HDAC) inhibitors) have shown promising results in preclinical models, and a limited number of agents, including the MCT1 inhibitor AZD3965 and the p300/CBP inhibitor CCS1477, have entered early-phase clinical trials primarily for safety and tolerability assessment. This review systematically summarizes the molecular mechanisms and enzymatic basis of lactylation, as well as its regulatory functions in core cancer hallmarks and the immune microenvironment, evaluates the translational prospects of targeting the lactate-lactylation axis, and discusses the key scientific questions and future research directions currently facing the field.

Keywords: lactate; lactylation; post-translational modification; targeted therapy; tumor immune microenvironment; tumor metabolic reprogramming

DOI: https://doi.org/10.3390/cimb48090926

Cancer Treat Res Commun. 2026 Sep 19. pii: S2468-2942(26)00287-X. [Epub ahead of print]49 101376

Metabolic Reprogramming Of Macrophages In Breast Cancer: Mechanisms And Therapeutic Implications.

Jiaoyu Zhang, Rui Yang.

As key immune cells in the tumor microenvironment (TME), macrophages polarize into pro-inflammatory M1 or anti-inflammatory M2 phenotypes, with their functional states tightly linked to metabolic pathway dynamics. This review comprehensively examines macrophage metabolic reprogramming in glycolysis, lipid metabolism, glutamine metabolism, the pentose phosphate pathway (PPP), mitochondrial function, the tricarboxylic acid (TCA) cycle, and amino acid metabolism, while exploring their implications for breast cancer's immune microenvironment and therapeutic approaches. In M1 macrophages, glycolysis is significantly enhanced, promoting the inflammatory response through lactate accumulation and reactive oxygen species (ROS) production. Simultaneously, the TCA cycle is disrupted at the citrate and succinate nodes, leading to the accumulation of metabolic intermediates and further strengthening the pro-inflammatory phenotype. On the other hand, M2 macrophages depend on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO). They regulate epigenetic modifications through metabolites such as alpha-ketoglutarate (α-KG) to maintain anti-inflammatory and tissue repair functions. Breast cancer cells reprogram macrophages via glutamine competition and exosome secretion, driving M2 polarization to support tumor progression. Different molecular subtypes exhibit distinct metabolic features: triple-negative breast cancer (TNBC) shows high glycolytic activity and glutamine addiction, whereas hormone receptor-positive breast cancer relies more on exogenous amino acid uptake. Targeting glycolysis or glutamine metabolism can revert tumor-associated macrophages (TAMs) to an anti-tumor M1-like state, boosting immunity. Although metabolic intervention strategies (such as inhibiting key enzymes hexokinase 2 (HK2), glutaminase (GLS), or fatty Acid Binding Protein 4 (FABP4)) show therapeutic potential, existing studies still have limitations: the compensatory effects between metabolic pathways, tumor heterogeneity, and insufficient clinical translation. Emerging strategies, including metabolic checkpoint targeting, CAR-macrophages (CAR-M), and biomimetic nanocarrier-based delivery systems, hold promise for overcoming these challenges. In summary, in-depth elucidation of the molecular mechanisms underlying macrophage metabolic reprogramming and their metabolic crosstalk with breast cancer cells will provide new insights and novel therapeutic targets for the precise immunometabolic therapy of breast cancer.

Keywords: Breast cancer; Macrophage; Metabolic reprogramming; Tumor microenvironment

DOI: https://doi.org/10.1016/j.ctarc.2026.101376