The mechanisms and roles of selective autophagy SQSTM1/p62 in cancer

SQSTM1/p62 is a multifunctional selective autophagy receptor and stress-responsive scaffold protein that integrates autophagy, oxidative stress responses, inflammation, and metabolic signaling. Initially characterized as an autophagic adaptor for ubiquitinated cargo, SQSTM1/p62 is now recognized as a central signaling hub that shapes tumor initiation, progression, metastasis, and therapeutic resistance. Its diverse biological activities arise from a modular domain architecture, dynamic post-translational modifications, and context-dependent interactions with key regulators including LC3, KEAP1, TRAF6, and mTORC1-associated components. In cancer, SQSTM1/p62 can exert both tumor-suppressive and tumor-promoting effects, depending on the cellular lineage, stage of tumorigenesis, autophagic competence, subcellular localization, and microenvironmental context. In this review, we summarize the structural basis of SQSTM1/p62 function, the multilayered mechanisms regulating its expression and activity, and the major signaling pathways organized by SQSTM1/p62 in tumor cells and the tumor microenvironment. We further discuss recent progress in pharmacological targeting of SQSTM1/p62 and highlight the challenges of selectively inhibiting oncogenic SQSTM1/p62 signaling without disrupting its essential physiological functions. Collectively, this review positions SQSTM1/p62 as a context-dependent molecular integrator and a promising, yet complex, therapeutic target in cancer.