Photo-metallo-immunotherapy: Fabricating Chromium-Based Nanocomposites to Enhance CAR-T Cell Infiltration and Cytotoxicity against Solid Tumors

The infiltration and cytotoxicity of chimeric antigen receptor (CAR)-T cells are crucial for effective elimination of solid tumors. While metallo-immunotherapy is a promising strategy that can activate the antitumor immunity, its role in promoting CAR-T cell therapy remains elusive. We have previously reported the first single-element nanomaterial based on chromium nanoparticles for cancer photo-metallo-immunotherapy. We report herein an extended study using biodegradable polydopamine as a versatile carrier for these nanoparticles, enabling synergistic CAR-T cell therapy. The results showed that these nanocomposites with or without further encapsulation of the anticancer drug alpelisib could promote the CAR-T cell migration and antitumor effect. Upon irradiation with near-infrared light, they caused mild hyperthermia that could "warm" the "cold" tumor microenvironment. The administration of B7-H3 CAR-T cells to NOD severe combined immunodeficiency gamma mice bearing a human hepatoma or PIK3CA-mutated breast tumor could significantly inhibit the tumor growth after the induction of tumor hyperthermia by the nanocomposites and promote the secretion of serum cytokines, including IL-2, IFN-γ, and TNF-α. The trivalent Cr ions, which are the major degradation product of these nanocomposites, could increase the CXCL13 and CCL3 chemokine expressions to generate tertiary lymphoid structures in the tumor tissues, facilitating the CAR-T cell infiltration. This article is protected by copyright. All rights reserved.