Chemotherapy-induced DNA Release Modulates Antitumor Immune Response

Chemotherapy induces the release of damage-associated molecular patterns (DAMP) from treated cells, yet how this affects antitumor immunity remains unclear. In this study, Zhang, Huang, Yang, and colleagues deciphered the roles of tumor-derived DNA fragments in modulating immune responses. Analysis of human breast cancer samples following treatment with anthracycline revealed distinct immunophenotypes. The immune-promoting (IP) phenotype was characterized by infiltration of CD4+ Th1 and activated CD8+ T cells, high expression of interferon (IFN)-stimulated genes and costimulatory receptors, and better response to chemotherapy. The immune-suppression (IS) phenotype was marked by high regulatory T cell (Treg) infiltration, expression of inhibitory molecules PD-L1 and IDO, and poor response to chemotherapy. Tumor DNA isolated from samples in the IP group promoted IFNβ production, cGAS–STING signaling, and costimulatory receptor expression in monocyte-derived dendritic cells (moDC) and macrophages (MDM), and suppression of the DNA sensor cGAS abolished this upregulation. Conversely, tumor DNA derived from IS samples enhanced caspase 1 cleavage, IL1β production, and inhibitory molecule expression by moDCs and MDMs in an AIM2-dependent manner. Levels of MSH2, a mismatch repair protein, were reduced in the IP group, leading to enrichment of CA repeats in released DNA. Consistently, CA-rich DNA released by cells lacking MSH2 showed heightened affinity for cGAS, leading to cGAS–STING signaling in moDCs and subsequent T-cell activation. Mutation of the CA-repeat binding residues on cGAS abolished downstream signaling. CA repeat-deficient DNA released by wild type cells showed preferential binding to AIM2, activating the inflammasome and Tregs, which was reversed by inhibition of IDO or IL1β. Mouse mammary tumors showed heightened chemosensitivity and increased antitumor immune responses following IL1β blockade or MSH2 knockout. Moreover, intratumoral injection of CA-rich DNA inhibited tumor growth and synergized with anti–PD-L1 therapy. High CA-repeat DNA levels were found to correlate with elevated IFNβ production, CD4+ and CD8+ T cell infiltration, chemosensitivity, and survival in patients with breast cancer. Altogether, this study demonstrates that different DNA fragments released by chemotherapy-treated cancer cells trigger different signaling pathways and immune responses.Zhang X, Huang P, Chen H, Yang C, Yang Y, Liu Y, et al. Chemotherapy-induced CA-repeat DNA fragments in breast cancer trigger antitumor immune responses. Nat Immunol 2025;26:1931–45.Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.