Protein post-translational modification networks in cancer drug resistance: From mechanisms to precision targeting

The development of therapy resistance remains a principal obstacle in oncology, driven by mechanisms beyond genetic mutations. Protein post-translational modifications (PTMs) are dynamic regulators that reprogram protein function, stability, and interactions. They establish a multifaceted defense system against chemotherapy, targeted therapy, and immunotherapy. This review systematically delineates how key PTMs—including phosphorylation, ubiquitination, methylation, lactylation, glycosylation, acetylation, palmitoylation, SUMOylation, and succinylation—orchestrate resistance by remodeling DNA damage repair, metabolic pathways, proteostasis, and immune checkpoint signaling. The review highlights complex PTM crosstalk—through competition, cooperation, and dependency—as a mechanism that can generate robust and adaptable resistance networks. We further evaluate emerging therapeutic strategies designed to target this network, such as proteolysis-targeting chimeras (PROTACs), molecular glues, and rationally designed combination therapies, alongside the promise of nanoparticle delivery and AI-driven diagnostics. Finally, key translational barriers are discussed, and systems-level characterization of PTM networks is proposed as a prerequisite for mechanism-guided therapeutic development.