Oncogenic KRAS Rewires Stress Granule Dynamics: Mechanisms and Therapeutic Opportunities.

Abstract

Stress granules (SGs) are dynamic, membrane-less structures that form in response to various cellular stresses, including metabolic, oxidative, and therapeutic challenges. They function as adaptive hubs and reorganize protein synthesis and signaling networks to help cells survive under stress. In cancer, these condensates are often hijacked to support survival and therapy resistance. SGs can sequester proapoptotic factors, buffer metabolic- and treatment-induced stress, and stabilize transcripts that promote cell survival, collectively contributing to tumor aggressiveness and resistance to therapy. Their formation relies on protein-RNA interactions, phase separation, and posttranslational modifications, which tumor cells exploit to maintain SGs even when normal stress conditions trigger their disassembly. This creates a protective pool of mRNAs and proteins that allows rapid adaptation to stress. Emerging therapeutic strategies that disrupt SG assembly, interfere with the adaptive functions of SGs, or accelerate SG clearance have shown promise in sensitizing tumors to treatment. This review summarizes the current understanding of SG dynamics, illustrating how cancer cells exploit these structures to survive stress. We focus specifically on KRAS-driven cancers, where persistent oncogenic signaling enhances SG formation and stability, making these condensates critical mediators of tumor adaptation. Targeting SG formation, maintenance, or associated stress-response pathways represents a promising approach to enhance therapeutic efficacy and improve long-term outcomes in cancers driven by sustained cellular stress.