Cold and hot tumors: immunological determinants, cancer-immunity cycle dysregulation, and nanotechnology-driven therapeutic approaches

Abstract

Cancer remains a major global health burden and the second leading cause of mortality worldwide. Recent advances in cancer immunotherapy have emphasized the critical role of the tumor microenvironment (TME) in determining therapeutic outcomes, leading to the classification of tumors into immunologically “hot” and “cold” phenotypes. Cold tumors are characterized by low immunogenicity, limited immune cell infiltration, and a highly immunosuppressive microenvironment, resulting in poor prognosis and resistance to immune checkpoint inhibitors. Despite the development of multiple immunotherapeutic strategies, effective activation of antitumor immunity in cold tumors remains a major clinical challenge. Current approaches aim to initiate immune responses through priming strategies such as cancer vaccines and adoptive T-cell transfer, while simultaneously overcoming immunosuppressive signaling via immune checkpoint blockade. Additional strategies include depletion of myeloid-derived suppressor cells and enhancement of co-stimulatory pathways. However, these approaches are often limited by inefficient delivery, poor tumor penetration, and systemic toxicity. Nanotechnology has emerged as a promising platform for tumor microenvironment reprogramming. Nanocarriers enable targeted delivery of immunomodulatory agents, enhance antigen presentation, and improve immune activation while overcoming biological barriers such as dense stroma and abnormal vasculature. By integrating nanotechnology with immunotherapy, new opportunities arise to convert cold tumors into hot, immune-responsive phenotypes, thereby improving therapeutic efficacy and clinical outcomes.