Recent advances in preclinical studies combining hyperthermia therapy with novel immune checkpoint targeting agents.

Hyperthermia has been used as an adjuvant therapy alongside radiotherapy and chemotherapy for cancer treatment in some countries. However, since the 2000s, growing evidence has indicated that hyperthermia exerts regulatory effects not only on cancer cells but also on stromal immune cells and the research interest in this topic has grown notably in the current "era of immunotherapy". Of particular interest to oncoimmunologists and hyperthermia researchers, recent studies have shown that hyperthermia modulates the expression of a wide range of immune checkpoint and co-stimulatory molecules. In addition to the PD-1/PD-L1 and CTLA-4/CD80/CD86 checkpoints previously reported and intensively discussed in existing reviews, recent studies indicate that hyperthermia exerts a broader regulatory effect on many other checkpoint and co-stimulatory molecules, include TIGIT/CD155, Tim-3/Gal-9, OX40/OX40L, and 4-1BB/4-1BBL on T cells, CD47/SIRPα on macrophages, and CD40/CD40L on dendritic cells. The present review aims to provide a complementary update, focusing specifically on recent advances in understanding how hyperthermia regulates the expression of these newer targets, as well as preclinical evidence for combining hyperthermia with novel therapeutic agents targeting these molecules. The insights gained from these preclinical studies could serve as a valuable foundation for future experimental investigations and clinical translation.