Thymosin Alpha-1 Restores Chemotherapy-Induced Antitumor Immunity by Chaperoning a MicroRNA Ligand of TLR7 in Dendritic Cells

Abstract Chemotherapy induces cancer cell apoptosis and the release of apoptotic bodies (AB) that are poorly immunogenic or immunosuppressive, creating a major barrier to the success of coadministered or second-line immunotherapies. In this study, we found reduced circulating levels of thymosin alpha-1 (Tα-1), a key endogenous peptide hormone with immunomodulatory activity, after chemotherapy treatment in patients with multiple types of cancer and in mice bearing established tumors. Tα-1 bound to tumor ABs and interacted with AB-borne microRNAs, including miR-146a-5p, following the phagocytosis of ABs into the endolysosomal compartment of dendritic cells (DC). The interaction with Tα-1 protected miR-146a-5p from lysosomal RNase A–mediated degradation, allowing miR-146a-5p–mediated activation of Toll-like receptor 7 (TLR7) that licenses DC maturation, migration to tumor-draining lymph nodes, and presentation of tumor antigens to activate tumor-specific CD8+ T cells. Therapeutic Tα-1 supplementation produced strong synergy with chemotherapy to control established tumors in mice with high miR-146a-5p expression in a TLR7-dependent manner. These findings establish Tα-1 as a pivotal endogenous microRNA chaperone that unlocks a critical limiting step of DC licensing, empowering robust antitumor immunity after chemotherapy. Significance: Tα-1 promotes miR146a-5p-mediated TLR7 signaling in dendritic cells to enhance chemotherapy-induced immunity, offering a foundation for developing Tα-1-based approaches to elicit or amplify immune responses against diverse tumors.