Progressive metabolic adaptation of tumor cells enables a thriving tumor microenvironment in which immune cells have diminished killing ability. However, whether and how this adaptation plays an active role in lymph node (LN) metastasis of lung cancer remains unclear.

We collected 37 matched samples of primary tumors, metastatic LNs (MetLNs), uninvolved LNs (uiLNs), and peripheral blood from 10 patients with lung cancer. These samples were profiled with single-cell RNA sequencing, T cell receptor/B cell receptor (TCR/BCR) sequencing, and spatial transcriptomics, capturing 671,467 cells in total. Modulator of Cytochrome C Oxidase during Inflammation (MOCCI)-dependent enhancement of oxidative phosphorylation (OXPHOS) and LN metastasis was demonstrated in vivo and in vitro, and its association with adverse prognosis was validated in an independent cohort from Fudan University Shanghai Cancer Center (n = 875). Spatial neighborhood and ligand–receptor analyses were used to examine primary LN metastatic cancer cell (PLMC)–immune interactions.

A PLMC subpopulation, characterized by MOCCI-driven OXPHOS reprogramming, was identified. MOCCI increased OXPHOS and promoted LN metastasis in vivo and in vitro, and higher MOCCI levels correlated with poorer prognosis in the cohort. In MetLNs, follicular helper T cells (Tfh) were significantly elevated but exhibited dysfunctional antigen-presentation programs, whereas naïve and memory B cells were enriched yet showed greater clonal diversity with blunted clonal expansion. Spatial analyses linked these features to MOCCI⁺ PLMCs, which, via GDF15-TGFBR2 axis signaling, drive Tfh exhaustion and suppress adjacent B-cell activation.

This study delineated transcriptional differences between primary tumors and MetLNs in lung cancer, thereby providing a foundation for further exploration of LN metastasis.