Abstract: Autophagy is a highly evolutionary conserved metabolic pathway, through which metabolic products of cells and necrotic organelles are degraded into lysosomes and then recycled. Autophagy plays an important role in tumor formation, progression, and metastasis, and even determines the prognosis. Multifunctional protein p62/SQSTM1 not only participates in the degradation process as an important selective autophagy receptor, but also plays an essential key role in the regulation of multiple key signaling pathways. Thus, several studies have highlighted its promising effect in the tumors and tumor microenvironment. Understanding the structure, function, and mechanism of p62/SQSTM1 will provide new potential targets for anti-cancer strategies based on pharmacological modulation of autophagy targeting.