HSPG2-NID2 Axis mediates immunosuppression and progression in gastric cancer

Gastric cancer represents a leading cause of cancer-related death worldwide, featuring complex pathogenesis and pronounced heterogeneity. Immunotherapy has recently demonstrated considerable clinical benefit for a subset of gastric cancer patients; however, its efficacy as a monotherapy is constrained by both primary and acquired resistance. Tumor immune evasion is recognized as a pivotal mechanism underlying immunotherapy failure. This investigation centers on the extracellular matrix component heparan sulfate proteoglycan 2 (HSPG2) and delineates its function and mechanistic involvement in gastric cancer progression and immune microenvironment modulation. Integrative bioinformatic analyses and clinical validation revealed a significant upregulation of HSPG2 in gastric cancer tissues, which correlated strongly with adverse patient outcomes and more aggressive clinicopathological characteristics. Functional assays demonstrated that HSPG2 overexpression enhances cancer cell proliferation and confers chemoresistance. Mechanistically, HSPG2 was found to facilitate gastric cancer progression by upregulating the basement membrane glycoprotein nidogen-2 (NID2) expression, leading to consequent activation of the Phosphoinositide 3-Kinase/ Protein Kinase B (PI3K/AKT) signaling cascade. Exploratory immune profiling substantiated that the HSPG2/NID2 axis suppresses CD4 + T cell recruitment and function, drives macrophage polarization towards an immunosuppressive M2 phenotype, and downregulates key cytotoxic effectors including interferon-γ and granzyme B, collectively fostering an immune-suppressive niche. In conclusion, this study establishes a novel role for HSPG2 in driving tumor proliferation, chemoresistance, and immune evasion in gastric cancer via the NID2/AKT signaling axis, thereby nominating the HSPG2/NID2 pathway as a promising prognostic indicator and a potential therapeutic target for immunotherapy.