Comprehensive pan-cancer analysis of p62 reveals its contribution to shaping tumor microenvironment and anti-tumor immunity.

[UNLABELLED] Sequestosome 1 (p62/SQSTM1) is a multifunctional adaptor protein whose dysregulation promotes tumorigenesis through autophagy, metabolic reprogramming, and immune modulation. However, its role across cancer types and impact on the tumor immune microenvironment remain poorly defined. Here, we performed a comprehensive pan-cancer analysis to delineate the molecular and immunological landscape of p62 across human malignancies. TCGA analysis revealed rare mutations and limited prognostic impact of genomic alterations but marked transcriptomic upregulation in LIHC, LUAD, BRCA, KIRP, KICH, KIRC, and READ, correlating with poor survival, advanced stage, and higher T classification, particularly in BRCA and LUAD. Pathway analysis showed strong positive associations between p62 and metabolic adaptation and stress tolerance pathways, including oxidative phosphorylation, reactive oxygen species, and DNA repair, in most cancers. Notably, high p62 expression inversely correlated with immune cell infiltration in most epithelial cancers, such as BRCA, COAD, ESCA, HNSC, KIRC, LIHC, LUAD, LUSC, PAAD, PRAD, READ, THCA, while coinciding with elevated expression of immunosuppressive checkpoints such as PD-L1, B7-H3, EBAG9, PVR, and TGFB1, supporting a link between p62-driven metabolic remodeling and an immune-excluded tumor microenvironment. In contrast, GBM, LGG, OV, SARC, and TGCT showed positive correlations between p62 and immunoscore, with enrichment of interferon and pro-inflammatory pathways, reflecting a distinct immune-activated phenotype. Collectively, these findings identify p62 as a central regulator of tumor metabolism and immunity, suggesting that its context-dependent activity may dictate the balance between immune suppression and activation across cancers, and highlight two natural-product-derived PB1 inhibitors (ZINC70669789 and ZINC08877690) as promising candidates for therapeutic development.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1007/s12672-025-04135-1.