Figure 1.

A multi-functional adjuvant: Heating impacts the tumor microenvironment through intrinsic and extrinsic mechanisms, which could enhance immunotherapy.

Increased vascular perfusion and blood flow to the tumor occurs through both thermoregulatory signals, as well as changes in tumor metabolism, leading to increased HIF-1, which leads to increased ROS production and VEGF expression. Increased trafficking of CD8⁺ T cells occurs through heat-induced increases in E/P selectin and ICAM-1 on tumor blood vessels; increased TCR signaling and differentiation of naïve T cells to effector cells. Increased tumor cell-surface expression of MICA/B and upregulation of the ligand NKG2D on NK cells, thereby increasing NK cell cytotoxic potential. Increased functional activity of macrophages, dendritic cells, Increased release of HSPs into the extracellular environment, which stimulate downstream immune activity, and increased antigen presentation.