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

Abstract

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 T cells, activating the recruited T cells and ultimately eradicating the tumors. This innovative strategy represents a comprehensive approach to fine-tune the TME, significantly amplifying the effectiveness of cancer immunotherapy by exploiting the TRPV1 pathway and enabling in situ control of immunomodulation within the TME.

Function and mechanism of action of the TRPV1 channel in the development of triple-negative breast cancer

“…TRPV1 channels can be activated by heat (≥43°C) and have the potential to induce TME transformation by activating calcium signaling in immune cells and triggering increased secretion of immune factors [29]. Ngo et al [93] delivered capsaicin and ICI (BMS202) into the glutathione-rich TME simultaneously using nanotechnology. The release of capsai- The TRPV1 agonist receptor cannabidiol (CBD) activates TRPV1 channels, causing extracellular calcium ions to flow inward.…”

“…cin-activated TRPV1 in the TME enhanced the expression of PD-L1 on the surface of tumor cells and promoted the recruitment of T cells into the TME, increasing immunoreactivity. Simultaneously, BMS202 inhibited immune checkpoints on both tumor cells and T cells, activating the recruited T cells and resulting in the elimination of tumor cells [93,94]. In contrast, nanoparticle-mediated TRPV1 channel blockade in combination with hyperthermia improved heat immunotherapy efficacy in TNBC, and researchers have employed nanoparticle-mediated TRPV1 blockade to inhibit HSP70 expression in TNBC by suppressing HSF1.…”