Pan-cancer single-cell atlas of immunotherapy response identifies ZNF385A as a regulator of immune evasion in small cell lung cancer.

Abstract

Although immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape of solid tumors, response rates in patients with small cell lung cancer (SCLC) remain limited, and acquired resistance is highly prevalent. The underlying mechanisms of this immunotherapy resistance remain to be fully elucidated. Clinically, SCLC typically manifests as an "immune-cold" tumor, characterized by a paucity of CD8+ T cell infiltration and the rare formation of tertiary lymphoid structures (TLS). While DNA damage repair (DDR) is closely linked to innate immune responses, how DDR networks orchestrate the SCLC immune microenvironment remains obscure. In this study, we integrated single-cell transcriptomic data (comprising 344,447 high-quality cells) from six cancer types (BCC, CRC, HCC, HNSCC, iCCA, and SCLC). Our comparative analysis revealed a fundamental depletion of TLS-associated cellular subpopulations (e.g., CXCL13+ CD8+ T cells, HLA-DRB5+ B cells, and CXCL9+ dendritic cells) in SCLC, which was significantly correlated with aberrant DDR activity. Through high-dimensional weighted gene co-expression network analysis (hdWGCNA), we identified ZNF385A as the core hub gene within the DDR-associated module. ZNF385A is highly expressed in SCLC and is associated with poorer prognosis. In vitro, ZNF385A depletion suppressed SCLC cell proliferation and induced apoptosis, accompanied by R-loop accumulation and activation of cGAS-STING signaling, indicating a potential link between ZNF385A, genomic stability and tumor-intrinsic innate immune signaling. Collectively, these findings identify ZNF385A as a potential regulator associated with TLS deficiency and immune evasion in SCLC.