Dissecting origin factors of lymph node metastasis in non-small cell lung cancer via multimodal omics

Cancer metastasis accounts for the majority of cancer-related deaths and lymph node metastasis is critical in cancer staging and prognosis. However, the mechanisms involved in lymph node metastatic non-small cell lung cancer (NSCLC) remain unclear. Here, we delineate the cellular and spatial landscape of metastatic lymph nodes and their matched primary tumors in NSCLC using multimodal omics. In results, tumor core and peripheral regions respectively exhibit high stemness and elevated expression of immunoglobulins. Increased expressions of CD274 (PD-L1) are observed in the immunoglobulin-high malignant cells and SPP1+IFI30+ macrophages. Notably, residual and tertiary lymphoid structures are identified. However, their anti-tumor immunity is compromised by CXCL13+ T cell exhaustion and immune exclusion. Furthermore, we identify the ferroptosis signaling, with its key factor FTH1 showing strong associations with cancer cell stemness and metastasis. This study elucidates the mechanisms of metastasis and immune evasion in lymph node metastatic NSCLC, providing insights for targeted therapies. Lymph node metastasis is critical in cancer staging and prognosis. Here, the authors use multimodal omics to explore the tumor microenvironment in non-small cell lung cancer (NSCLC) and identify FTH1-relevant cancer stemness, CXCL13+ T cell exhaustion and immune evasion contribute to lymph node metastasis of NSCLC.