Turning cold tumors into hot tumors to ignite immunotherapy

The revolution in cancer immunotherapy, particularly through immune checkpoint inhibitors (ICIs), underscores the significant role of the tumor microenvironment (TME) in determining therapeutic outcomes. At the heart of this is the classification of tumors into “cold” and “hot”, which significantly influences the efficacy of immunotherapy. “Cold” tumors are characterized by scant immune cell infiltration and an immunosuppressive TME, which effectively evades immune detection and resists ICIs. In contrast, “hot” tumors, characterized by abundant immune cells and a proinflammatory environment, are more receptive to immunotherapeutic approaches. This review comprehensively examines the molecular and cellular foundations of the “cold” tumor phenotype, delving into the mechanisms of camouflage (impeding immune priming and infiltration), coercion (suppressing immune functions)​​, and ​​cytoprotection (resisting inflammatory death)​​ that contribute to maintaining immune silence. Furthermore, it critically evaluates emerging strategies for converting “cold” tumors to “hot”, immune-reactive entities, including the role of biomaterials in remodeling the TME to increase the effectiveness of immunotherapy. Through an in-depth exploration of these foundational mechanisms and therapeutic advancements, this review seeks to shed light on the way forward in cancer treatment, framing the transformation of “cold” tumors to “hot” tumors as a crucial approach to enhancing the reach of immunotherapy to a broader array of cancer types.