Harnessing the Power of IL-12: Revolutionizing Cancer Therapy with Combinatorial Strategies

Interleukin-12 (IL-12) is a potent immunostimulatory cytokine that enhances T cell and natural killer (NK) cell activation and promotes Th1-type immune responses. However, its clinical application as monotherapy has been hampered by systemic toxicity and limited efficacy. As a result, IL-12-based combination strategies have attracted increasing attention in cancer therapy. This review summarizes the immune regulatory mechanisms by which IL-12 remodels the tumor microenvironment and enhances antitumor immunity. We discuss recent preclinical and clinical advances in combining IL-12 with immune checkpoint inhibitors, chemotherapy, cellular therapies such as CAR-T cells, and cancer vaccines. In addition, emerging synergistic approaches involving targeted therapies and STING agonists are highlighted. Finally, we address current challenges and future directions, focusing on strategies to improve tumor specificity and minimize systemic toxicity. Overall, this review emphasizes IL-12 as a key immunomodulatory component in next-generation combination cancer therapies.