<p>The proteostasis network plays a pivotal role in enabling tumor cells to maintain protein homeostasis, mitigate proteotoxic stress, and promote tumor progression and resistance to therapeutic interventions. Targeting proteostasis has garnered considerable attention as a promising anti-cancer strategy, with potential to enhance the efficacy of various therapeutic modalities. In this review, we provide a comprehensive synthesis of the proteostasis regulatory network within tumor cells, elucidating the molecular mechanisms by which proteotoxicity induces cellular damage and death. Furthermore, we present the latest advancements in proteostasis-targeted strategies, offering an in-depth exploration of approaches to sensitize tumor cells to proteotoxic stress, overcome drug resistance, and improve the effectiveness of cancer immunotherapy and radiotherapy. By highlighting the key challenges and emerging research directions, this review aims to provide valuable insights into the development of novel proteostasis-targeted therapies.</p>