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ABSTRACTThe Src©\like adaptor 2 (SLA2) functions as a negative regulator of T cell receptor signalling. However, its involvement in the tumour microenvironment (TME) of gastric cancer (GC) remains unexplored. In this study, we found that SLA2 expression was significantly elevated in GC tissues, and a high level of SLA2 was associated with poor prognosis in GC patients. Bioinformatics analyses revealed a close association between SLA2 and TME in GC. Single©\cell RNA sequencing analysis indicated that SLA2 was significantly enriched in CD8+ T cells in GC tissues. Functional validation demonstrated that SLA2 overexpression contributed to the exhaustion of CD8+ T cells by suppressing their proliferation, upregulating the expression of exhaustion markers, reducing the secretion of effector cytokines (IFN©\¦Ã and TNF©\¦Á) and impairing cytotoxic function. SLA2 knockdown in in vitro©\generated exhausted CD8 T cells significantly alleviated T cell exhaustion. Mechanistically, we found that inverse promoter methylation and active histone marks (H3K27ac, H3K4me3 and H3K4me1) may regulate SLA2 expression. Our findings suggest that SLA2 may modulate the TME and promote immune evasion via CD8+ T cell exhaustion in GC.

AbstractBackgroundPeritoneal metastasis (PM) is one of the most challenging clinical problems in gastric cancer (GC), largely due to its high recurrence rate and poor response to current therapies. Increasing evidence indicates that remodeling of the extracellular matrix (ECM) plays an important role in therapeutic failure. However, how specific stromal¨Cimmune interactions contribute to PM heterogeneity and immunotherapy resistance remains unclear. In this study, we investigated how ECM composition¡ªparticularly the accumulation of hyaluronic acid (HA)¡ªinfluences the immune microenvironment and therapeutic responses in GC-associated PM.MethodsWe combined histopathological assessment, analyses of patient-derived specimens, single-cell transcriptomic profiling, and murine models of PM to delineate ECM remodeling patterns and immune cell dynamics in therapy-sensitive and therapy-resistant lesions. In addition, functional assays and pharmacological approaches were used to examine HA¨CCD44 signaling and its impact on CD4+ T cell differentiation and responsiveness to immune checkpoint blockade.ResultsTherapy-sensitive PM lesions were characterized by enrichment of elastic fibers, whereas therapy-resistant lesions showed collagen accumulation. Notably, HA deposition emerged as a key feature distinguishing these ECM states and was closely associated with differential therapeutic outcomes. Elevated HA levels activated CD44-dependent signaling in CD4+ T cells, driving regulatory T cell (Treg) differentiation through a CD44¨CIQGAP1¨CRAC1¨CSMAD3 signaling pathway and thereby establishing an immunosuppressive microenvironment. Importantly, pharmacological inhibition of CD44 reduced Treg expansion and markedly enhanced the antitumor efficacy of anti-PD-1 therapy in murine PM models.ConclusionsOur findings identify HA¨CCD44 signaling as a critical link between ECM remodeling and immune evasion in GC PM. Targeting ECM-driven immunosuppressive mechanisms may represent a promising strategy to overcome therapeutic resistance and improve the efficacy of immunotherapy in this aggressive disease.

Persistent infection with high-risk human papillomavirus (HR-HPV) is the primary cause of cervical cancer. Co-infection with HIV-1 increases the risk of cervical cancer progression 6-fold, despite adherence to antiretroviral therapy (ART). While chronic HIV-1 infection is known to cause inflammation, the paracrine effects of HIV-1-infected immune cells on cervical signaling remain unclear. We performed transcriptomics on cervical swabs from Kenyan women stratified by HIV-1 and cancer status, which revealed HIV-1 infection drove cancer-like gene expression in non-cancerous cervical cells. In parallel, global abundance proteomics and phosphoproteomics of cervical cancer cells exposed to HIV-1-infected human primary CD4+ T cell secretomes revealed altered MAPK, PI3K-AKT, cell cycle, and beta-catenin pathways. Concordantly, IRS1 was upregulated in both patient cervical samples and cultured cells. Our findings suggest HIV-1 dysregulates cervical cell signaling via paracrine mechanisms to phenocopy PIK3CA-activating mutations through IRS1-PI3K-AKT pathway activation. Our findings highlight IRS1 and the PI3K pathway as a potential therapeutic target for cervical cancer in women living with HIV-1.