Abstract While chemo-immunotherapy has been established as the frontline therapeutic regimen for extensive-stage small cell lung cancer (ES-SCLC), durable responses persist predominantly in a minor population of patients. This underscores critical need to elucidate underlying local tumor microenvironment and systematic immune profiles for biomarker discovery. In this phase II trial (ChiCTR2000038354), the efficacy, safety, and immune-genomic signatures of sintilimab (anti-PD-1 antibody) synergized with chemotherapy as first-line regimen for ES-SCLC were evaluated. The regimen demonstrated a median progression-free survival (PFS) of 6.9 months and median overall survival of 17.1 months, accompanied by a 12-month PFS rate of 16.9%, fulfilling the primary endpoint. Manageable grade 3 or 4 treatment-related adverse events developed in 27.3% (12/44) of patients. The exploratory study indicated a higher infiltration of CD4+/CD8+ CXCR5+ T follicle helper cells, CD8+CD103+ tissue-resident memory T cells, and B cells in tumor tissue, associated with better response and prognosis. The study also indicated the presence of tumor macrophages (CD68+CD163+CSF1R+SIGLEC5+) associated with immunotherapy resistance. Higher levels of monocyte-dendritic cells in pre-treatment peripheral blood mononuclear cells were found in durable clinical benefit group. Also, higher CD83, CD244, IL-12, and CD70, which are hallmarks of dendritic cells and activated T cells, were discovered by plasma proteomics to be connected with enhanced outcomes, while chemoattractant of macrophage, CSF-1, CCL3, CCL4, and IL-8, were found to predict a worse prognosis. Furthermore, a multimodal model was constructed and validated for stratifying ES-SCLC into high or low risk to predict the immunotherapy efficacy. This study sheds light on harnessing local and systematic immune profiles to better stratify patients with ES-SCLC for immunotherapy and putative combinational treatment.