Proteomic characterization of small cell lung cancer uncovers innate-adaptive immune dynamics and immunotherapeutic vulnerabilities

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine carcinoma with a poor prognosis and limited therapeutic advances. In this study, we performed deep proteomic profiling of 134 patients with resectable, limited-stage SCLC. We quantified over 10,000 proteins and delineated two distinct proteomic subtypes, PS1 and PS2, which exhibit divergent biological pathways, metabolic-immune features and clinical outcomes. The PS1 subtype exhibited enhanced neuroendocrine differentiation and proliferative signaling, correlating with poorer survival outcomes. In contrast, the PS2 subtype was characterized by concurrent activation of immune pathways and fatty acid metabolism, which was linkied to a more favorable prognosis. Further stratification of PS2 revealed two immune microenvironment clusters, IIS and IAS, with differential prognostic and therapeutic implications. The IAS cluster, characterized by robust adaptive immunity, was associated with favorable prognosis, while the IIS cluster, marked by heightened innate but deficient adaptive immunity, showed superior responsiveness to immune checkpoint blockade. Our study advances the understanding of SCLC heterogeneity and provides a clinically actionable proteomic taxonomy for subtype classification and therapy selection.