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 3+ 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.