Targeting cytokine/chemokine signaling to convert immunologically cold tumors into hot: Emerging strategies in cancer immunotherapy

The field of cancer immunotherapy has undergone significant advancements in recent years, leading to a paradigm shift in treatment methodologies. However, “cold” tumors, characterized by low immune cell infiltration and an immunosuppressive tumor microenvironment (TME), present considerable therapeutic challenges. In contrast to “hot” tumors, which exhibit vigorous immune activity and responsiveness to immune checkpoint inhibitors, “cold” tumors evade immune surveillance through mechanisms such as impaired antigen expression and restricted T-lymphocyte infiltration. This immune evasion is closely linked to the dysregulation of cytokines and chemokines, which shape the TME and orchestrate immune responses. This review delineates the immune escape mechanisms of cold tumors, with particular emphasis on the role of cytokines/chemokines in modulating the TME. Here we will explore advanced therapeutic strategies that employ engineered chemokines/cytokines ( e . g ., IL-2 muteins such as Neo-2/15, IL-15/IL-15R α complexes, and CAR-T cells expressing CXCL9/10), nanoparticle-based delivery systems ( e . g ., lipid nanoparticles, PLGA nanoparticles, and chitosan-based carriers for targeted cytokine/chemokine delivery), and combination therapies. These strategies aim to remodel the TME to enhance immune infiltration. Emerging therapies designed to transform cold tumors into immunologically active phenotypes through the modulation of cytokines and chemokines are discussed. Finally, the review highlights the ongoing challenges and future directions in using cytokine/chemokine modulation to overcome the limitations of current treatments, emphasizing their transformative potential in addressing the unmet needs of cancer immunotherapy. Cytokine/chemokine-based strategies, including nanoparticle delivery, gene transfer, combination with immunotherapy, and immune cell activation, collectively reprogram cold tumors and enhance anti-tumor immunity.