Spatial transcriptomics highlights B cells as key contributors to a complete and durable response to chemo-immunotherapy in a patient with resectable NSCLC.

Neoadjuvant chemo-immunotherapy has significantly improved the treatment landscape for patients with ALK/EGFR wt resectable non-small cell lung cancer (NSCLC), offering novel opportunities for translational and clinical investigations. By leveraging deep molecular profiling through spatial transcriptomics integrated with single-cell RNA-sequencing from public atlases, and serum proteomic profiling, we report a case of a patient with resectable NSCLC and a solitary synchronous brain metastasis showing a complete pathologic response after chemo-immunotherapy, and a durable event-free survival. The deep profiling of the tumor immune microenvironment of both pre-treatment brain metastasis and post-treatment primary lung tumor tissues unveiled a key role of B lymphocytes at different maturation state, spanning from naïve to plasma cells, in mediating tumor eradication. Notably, the formation of several tertiary lymphoid structures in the regression bed of post-treatment primary tumor was observed, suggesting the in situ generation of high-affinity antibody and specific immune memory response. This multimodal approach paves the way for the discovery of novel biomarkers at both tissue and systemic levels, fostering improved patient stratification and guiding clinical decisions on post-surgical treatment escalation or de-escalation.