The emerging roles of liquid–liquid phase separation in tumor immunity

Recent advancements in tumor immunotherapy, particularly PD-1 targeted therapy, have shown significant promise, marking major progress in tumor treatment approaches. Despite this, the development of resistance to therapy and mechanisms of immune evasion by tumors pose considerable obstacles to the broad application of immunotherapy. This necessitates a deeper exploration of complex immune signaling pathways integral to tumor immunity. This review aims to critically analyze the role of liquid-liquid phase separation (LLPS) within tumor immunity, specifically its impact on immune signaling pathways and its potential to foster the development of novel cancer therapies. LLPS, a biophysical process newly recognized for its ability to spontaneously segregate and organize biomacromolecules into liquid-like condensates through weak multivalent interactions, offers a novel perspective on the formation of signaling clusters and the functionality of immune molecules. The review delves into the micromolecular mechanisms behind the creation of signaling condensates via LLPS and reviews recent progress in adjusting signaling pathways pertinent to tumor immunity, including the T cell receptor (TCR), B cell receptor (BCR), immune checkpoints, and innate immune pathways such as the cGAS-STING pathway, stress granules, and the ADP-heptose-ALPK1 signaling axis. Furthermore, it considers the prospects of utilizing LLPS to generate groundbreaking cancer therapies capable of navigating past current treatment barriers. Through an extensive examination of LLPS's impact on tumor immunity, the review seeks to highlight novel therapeutic strategies and address the challenges and future directions in this rapidly evolving field.