Single-cell spatial proteomics of non-relapse small cell lung cancer identifies tumor microenvironment determinants of survival

Small cell lung cancer (SCLC) is characterized by high malignancy and early propensity for metastasis, and modest response to immunotherapy due to the immunosuppressive microenvironment. Surgical intervention has shown benefits in treating early-stage SCLC. However, most patients experience recurrence after surgery. The factors associated with relapse free survival in these patients remain unclear. We collected operation specimens from ten early-stage SCLC patients (N0M0), conducted long-term follow-up, and grouped them based on disease status. Subsequently, we performed a retrospective analysis using single-cell spatial imaging mass cytometry to explore the characteristics of tumor cells and differences in the tumor microenvironment, especially the single-cell constitute of immune cells, between the two groups. We found that, in early-stage SCLC, tumor cells display pronounced heterogeneity, both intra-group and inter-group. Patients with early recurrence are characterized by a distinct subpopulation of tumor cells with high Ki-67 expression. Non-relapse patients demonstrate better infiltration of M1 macrophages and stromal cells. Neighborhood analysis suggested that positive interactions between macrophages, stromal cells, and T cells with tumor cells may benefit patient prognosis. Additionally, recurrent tumor cells might enhance their metastatic capacity and remodel the microenvironment through upregulation of GranzymeB or reduction of c-Myc expression. In conclusion, SCLC tumor cells demonstrate tumor heterogeneity and microenvironmental changes in the early clinical stages. A higher proportion of M1 macrophages is associated with prolonged postoperative survival in early-stage SCLC patients. This research provides novel insights and evidence for treating and preventing postoperative recurrence in SCLC.