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Background Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine carcinoma with an immunosuppressive tumor microenvironment, characterized by low T-cell infiltration and reduced antigen presentation. While immune checkpoint blockade (ICB) combined with chemotherapy provides limited benefits, most patients do not achieve durable responses, underscoring the urgent need for novel strategies. Lurbinectedin, an approved second-line therapy for SCLC, is being evaluated in combination with PD-L1 blockade, yet its immunomodulatory effects remain largely unexplored.Methods To assess the immune impact of lurbinectedin, we analyzed matched SCLC tumor samples pre- and post-treatment using a 204-gene RNA Salah Targeted Expression Panel (STEP). A 7-marker multiplex immunofluorescence panel was applied to primary and metastatic tumor sites.Results Transcriptional level analysis by RNA STEP demonstrated multiple DNA-damage-related genes post-lurbinectedin treatment. Furthermore, our data represented the upregulation of markers for monocytes, and macrophages, B- and T-lymphocytes markers as well as an increase in subunits of TCR complex. Most interestingly our analysis revealed upregulation of multiple MHC-I/II genes along CD274 (PD-L1) gene expression post-lurbinectedin treatment. Multiplex immunofluorescence panel indicated a significant upregulation of infiltrating cytotoxic T cells in the tumor region of the lung along with an increase in CD19 +/CD138+ cells.We found a similar increase in cytotoxic T cell population in metastatic sites of SCLC tumors like liver and lymph nodes. Most interestingly, we observed an increase in the co-stimulatory response promoting CD3+ 4-1BB+ cells in lymph nodes. Investigating on the stroma region in the pre- and post-treated patient, both from primary site lung and metastatic sites we observed a significant upregulation of total-T cells, and helper-T cells along with an increased expression of CD19+ CD138+ indicating an increase in antigen-presenting cells. Encouragingly, we observed increased co-stimulatory receptor 4-1BB along with MHC-I and MHC-II markers in lymph-node stroma post-lurbinectedin treatment.Our study demonstrated increased efficacy of anti PD-L1 therapy in combination with lurbinectedin in a CD8+ T-cell dependent manner. Together, our data indicates that lurbinectedin treatment increases the immunogenicity of SCLC patient tumors by upregulating multiple immune markers including cytotoxic T-cells, co-stimulatory receptors, and MHC-I/II genes.Conclusions These findings highlight the potential of lurbinectedin to reprogram the SCLC tumor microenvironment, shifting it toward a more immunogenic state. By enhancing T-cell infiltration, antigen presentation, and co-stimulatory signaling, lurbinectedin may significantly improve patient responses to ICB. This study provides a strong rationale for combining lurbinectedin with ICB, offering new hope for improving clinical outcomes in patients with SCLC.