Blockage of HSP90 and IDO1 pathway by α-MSH modified nanoelicitor to dual-facilitate mild photothermal therapy

Mild photothermal therapy (PTT) kills tumors at low temperatures (<45 ​°C) with less non-specific thermal diffusion through adjacent normal tissues, making it a promising antitumor strategy. Although mild PTT can directly convert light energy into heat to kill tumors and indirectly induce immune cell death to prime the immune response, it simultaneously induces negative regulatory factors in the body to resist antitumor functions. In particular, the direct killing effects were reversed by the upregulation of heat shock protein 90 (HSP90) induced by mild PTT. The antitumor effects of T-cell-based immunotherapy counter indoleamine 2,3-dioxygenase1 (IDO1)-catalyzed kynurenine accumulation. Current studies have mainly focused on promoting direct killing effects or utilizing the priming immune response to strengthen the immunotherapy of mild PTT. Therefore, it is necessary to investigate whether the simultaneous promotion of direct killing and indirect immune activation would synergistically maximize mild PTT efficacy. This study reports on the development of a tumor-targeting nanoelicitor, α-MSH-GA/IR780/1-MT-Liposome (M-GIM-Lip), by co-loading the photothermal agent IR780, HSP90 inhibitor geldanamycin, and IDO1 inhibitor 1-MT into liposomes with a melanoma-specific target ligand α-MSH modification. After accumulating in the tumor, the M-GIM-Lip could significantly inhibit tumor progress by combinate blockage of HSP90 and IDO1 pathways at 41 ​°C treatment of mild PTT. The study offers an innovative co-regulation strategy for enhancing the antitumor effects of mild PTT.