Cancer remains a major global health challenge, largely due to its biological heterogeneity and the capacity of tumor cells to adapt under metabolic and environmental stress. Lipid metabolism has increasingly been recognized as a contributor to tumor progression and treatment response. Proprotein convertase subtilisin/kexin type 9 (PCSK9), widely known for regulating low-density lipoprotein (LDL) receptor turnover and systemic cholesterol levels, has recently been implicated in cancer biology. Emerging evidence shows that PCSK9 influences processes such as cell survival, MHC-I-mediated immune recognition, membrane receptor trafficking, and cellular stress responses, indicating roles that extend beyond its canonical metabolic function. These mechanisms also raise the potential relevance of PCSK9 to affect treatment tolerance and drug responsiveness. This review summarizes current knowledge on the biological functions of PCSK9 in cancer and examines how these pathways may have implications for therapeutic resistance. © 2025 by the authors.