1 research outputs found
Immunomodulatory Prodrug Micelles Imitate Mild Heat Effects to Reshape Tumor Microenvironment for Enhanced Cancer Immunotherapy
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