From "cold" to "hot": Icariin reshapes the tumor immune microenvironment through programmed cell death

Global burden of cancer continues to rise, yet advanced therapeutic strategies, including immune checkpoint inhibitors, often show limited efficacy against immunosuppressive "cold" tumors, a major hurdle in tumor immunotherapy. Icariin, a natural flavonoid derived from the traditional Chinese medicinal herb Epimedium, which has garnered significant scientific interest due to its multi-targeted anticancer and the immunomodulatory properties. This comprehensive review systematically delineates the pivotal role of icariin in remodeling the tumor microenvironment through a dual-action mechanism: it directly suppresses immunosuppressive populations such as myeloid-derived suppressor cells and M2-polarized tumor-associated macrophages, while concurrently promoting the CD8⁺ T cell infiltration, facilitating tumor vascular normalization, and inhibiting cancer-associated fibroblasts. In parallel, icariin strategically triggers key programmed cell death pathways, including immunogenic cell death and ferroptosis, thereby potentially initiating an in situ vaccination effect that may contribute to the stimulation of adaptive immunity. These coordinated mechanisms collectively establish a molecular foundation for the icariin's capacity to convert "cold" tumors into "hot" ones, and underscore its potential to synergistically enhance the efficacy of the immune checkpoint inhibitors and conventional chemoradiotherapy. In summary, icariin represents a promising but still experimental natural immunomodulatory agent; its clinical translation will require rigorous validation through well‑designed human trials, and its primary value may lie in combination regimens rather than as a standalone therapeutic.