Targeting DNA damage repair pathway and CCR2⁺ myeloid cell to overcome radioimmunotherapy resistance in small cell lung cancer

Background: Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine carcinoma characterized by rapid progression and a high relapse rate. Although the combination of immune checkpoint inhibitors (ICIs) with radiotherapy (RT) has improved patient outcomes, acquired resistance remains inevitable. This study aims to elucidate the underlying mechanisms of radioimmunotherapy resistance and explore potential novel strategies. Methods: We established a murine SCLC model of acquired radioimmunotherapy resistance by subjecting tumor-bearing mice to multiple cycles of RT + ICI until resistance developed. Subsequently, longitudinal single-cell RNA sequencing (scRNA-seq) analysis of tumor specimens was performed to validate the findings. The DNA damage repair (DDR) pathway was investigated using Western Blot, ELISA, and Transwell assays. The efficacy of adding PARP inhibitor (PARPi) to RT+ICI was evaluated in vivo . Results: Analysis of the radioimmunotherapy-resistant murine SCLC model revealed that enhanced DDR activity, elevated CCL2 secretion, and increased of infiltration of CCR2⁺ myeloid-derived suppressor cells (MDSCs), which were further validated by longitudinal scRNA-seq. Targeting the CCL2-CCR2 axis significantly delayed tumor relapse following RT + ICI treatment. Next, i n vitro , combining PARPi with RT synergistically suppressed DDR activation and inhibited CCL2-dependent MDSC migration. In vivo , concurrent administration of PARPi with RT + ICI was essential for achieving better tumor control and survival benefit compared with RT + ICI treatment, whereas delayed intervention of PARPi proved ineffective. Tumor microenvironment analysis demonstrated that the triple therapy (RT + ICI + concurrent PARPi) effectively suppressed the DDR pathway, significantly reduced CCR2⁺ MDSC infiltration, and increased effector T cell recruitment. Conclusion: DDR-driven CCL2 secretion recruits CCR2⁺ MDSCs to mediate radioimmunotherapy resistance in SCLC. PARPi disrupts this axis through dual blockade of tumor DDR and MDSC recruitment. Our data revealed that the combination of concurrent PARPi with radio-chemo-immunotherapy as first line therapy in ES-SCLC is worth exploring and a prospective clinical trial is ongoing (NCT06217757).