Pan-cancer analysis of SQSTM1/p62 reveals its comprehensive contribution to shaping tumor microenvironment and anti-tumor immunity

Sequestosome 1 (SQSTM1)/p62 is a multifunctional protein involved in diverse physiological processes, and it has been evidenced that its dysregulation implicated in tumorigenesis. Using TCGA pan-cancer data, we analyzed p62 genomic alterations, expression patterns, and clinical relevance. Our results show that p62 mutations and copy number variations (CNVs) are rare, suggesting that prognostic significance of this gene is poor. However, p62 gene expression was significantly elevated in several cancers, including BRCA and LUAD , where it correlated with poorer overall survival and advanced tumor stages. Pathway analyses showed a strong association between p62 and oncogenic features, such as oxidative phosphorylation, reactive oxygen species (ROS), increased tumor mutation burden (TMB), and microsatellite instability (MSI). Intrestingly, p62 expression was inversely associated with immune cell infiltration and positively correlated with immunosuppressive markers, suggesting its role in fostering an immunosuppressive tumor microenvironment (TME) in most types of cancer. Therefore, p62 plays a pivotal role in cancer as both a driver of oncogenesis and a modulator of the TME, supporting its potential as a biomarker and therapeutic target to enhance the efficacy of immunotherapies, particularly immune checkpoint inhibitors (ICIs). Through docking-based virtual screening, we finally identified four natural-product-derived inhibitors targeting the PB1 domain of p62, which is essential for its self-oligomerization, with favorable pharmacokinetic profiles.