Abstract / Summary
The reasons why some patients with small-cell lung cancer (SCLC) benefit from chemotherapy and immunotherapy, while others rapidly develop resistance, are still undefined. Despite improved outcomes with platinum-based chemotherapy combined with immune checkpoint inhibitors have been correlated to activation of the innate immunity, the role of immune cells as potential markers of response is incompletely understood. Here, we characterized the transcriptional and functional landscape of circulating natural killer (NK) cells in patients with SCLC at baseline and after cisplatin treatment, stratified by clinical response. By integrating transcriptomics, cytokine profiling, and high-dimensional flow cytometry, we identified distinct NK cell subsets and developed an NK immune-fitness signature validated in independent intratumoral cohorts. At baseline, responders exhibited strong interferon signaling, enrichment of CD16 + cytotoxic NK1 cells, and enhanced activation, correlating with prolonged progression-free survival, whereas non-responders showed a quiescent NK3-dominant profile. Following treatment, responders displayed further expansion of cytotoxic NK1 cells, while non-responders shifted toward reduced functional capacity. Analyses of immune infiltrate confirmed CD16, but not CD56, as a predictor of improved survival. Integration of effector and evasion programs defined four immunological states, with the infiltrated-active phenotype associated with the most favorable outcomes. These findings show that both baseline NK cell fitness and therapy-induced remodelling may shape clinical response and identify CD16 + NK cells as a potential clinically actionable biomarker to guide patient stratification and also inform NK-targeted new therapeutic strategies.