Immunotherapy, a groundbreaking approach to cancer treatment, harnesses the body’s immune system to recognize and eliminate cancer cells. Among the most successful strategies is immune checkpoint blockade (ICB), which uses antibodies to inhibit immune checkpoint proteins and thereby restore anti-tumor immune responses. Despite its clinical success, ICB benefits only a subset of patients, underscoring the need to better understand tumor immune evasion mechanisms and develop strategies to improve therapeutic efficacy. Recent studies have shown that low T-cell infiltration in the tumor microenvironment, commonly referred to as a “cold tumor”, can significantly limit the effectiveness of ICB therapy. Converting these cold tumors into “hot tumors” with robust T-cell infiltration is therefore a key step toward improving treatment outcomes. Epigenetic regulation, particularly through histone deacetylation (HDAC), has emerged as an important factor in shaping the tumor immune landscape. Treatment with HDAC inhibitors and other epigenetic drugs has demonstrated potential in reprogramming the tumor microenvironment to favor immune activation and enhance ICB responses. In this project, we aim to investigate the potential of natural compounds as novel agents to enhance cancer immunotherapy by modulating epigenetic and immune pathways. Natural products, with their diverse bioactive properties, may offer new therapeutic avenues to transform immunologically “cold” tumors into “hot” ones, thereby boosting the success of ICB.