2. Academic Validation
  3. Immunomodulatory Prodrug Micelles Imitate Mild Heat Effects to Reshape Tumor Microenvironment for Enhanced Cancer Immunotherapy

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

  • ACS Nano. 2024 Feb 20;18(7):5632-5646. doi: 10.1021/acsnano.3c11186.
Thi-Lan-Huong Ngo 1,  Kuan-Lin Wang 1 2,  Wen-Yu Pan 3 4,  Ting Ruan 2,  Yu-Jung Lin 1
Affiliations

Affiliations

  • 1 Research Center for Applied Sciences, Academia Sinica, Taipei, 115201, Taiwan.
  • 2 School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, 242062, Taiwan.
  • 3 School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, 110301, Taiwan.
  • 4 Ph.D. Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, 110301, Taiwan.
PMID: 38344992 DOI: 10.1021/acsnano.3c11186
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.

Keywords

TRPV1; capsaicin; heat sensor; immune checkpoint inhibitor; immunomodulation; tumor microenvironment.

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