Immunomodulatory Prodrug Micelles Imitate Mild Heat Effects to Reshape Tumor Microenvironment for Enhanced Cancer Immunotherapy

作者：Thi-Lan-Huong Ngo, Kuan-Lin Wang, Wen‐Yu Pan, Ting Ruan, Yu‐Jung Lin · 发表于：ACS Nano · 年份：2024 · DOI：10.1021/acsnano.3c11186 · 被引用次数：16 · 研究领域：Cancer, Stress, Anesthesia, and Immune Response、Ion Channels and Receptors、Nanoplatforms for cancer theranostics

Physical stimulation with mild heat possesses the notable ability to induce immunomodulation within the tumor microenvironment (TME). It transforms the immunosuppressive TME into an immune-active state, making tumors more receptive to immune checkpoint inhibitor (ICI) therapy. Transient receptor potential vanilloid 1 (TRPV1), which can be activated by mild heat, holds the potential to induce these alterations in the TME. However, achieving precise temperature control within tumors while protecting neighboring tissues remains a significant challenge when using external heat sources. Taking inspiration from the heat sensation elicited by capsaicin-containing products activating TRPV1, this study employs capsaicin to chemically stimulate TRPV1, imitating immunomodulatory benefits akin to those induced by mild heat. This involves developing a glutathione (GSH)-responsive immunomodulatory prodrug micelle system to deliver capsaicin and an ICI (BMS202) concurrently. Following intravenous administration, the prodrug micelles accumulate at the tumor site through the enhanced permeability and retention effect. Within the GSH-rich TME, the micelles disintegrate and release capsaicin and BMS202. The released capsaicin activates TRPV1 expressed in the TME, enhancing programmed death ligand 1 expression on tumor cell surfaces and promoting T cell recruitment into the TME, rendering it more immunologically active. Meanwhile, the liberated BMS202 blocks immune checkpoints on tumor cells and...