What does this research mean for the field?

MOCCI-driven oxidative phosphorylation enhances lymph node metastasis in lung cancer and correlates with poorer prognosis. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This research investigates the role of metabolic adaptation in lung cancer lymph node metastasis and its impact on immune function.

February 22, 2026Open Access

Single-cell and spatial transcriptome analyses reveal tumor immunometabolism in lymph node metastasis of lung cancer

Key Points

This research investigates the role of metabolic adaptation in lung cancer lymph node metastasis and its impact on immune function.
Analyzed 37 matched samples from lung cancer patients, including primary tumors and metastatic lymph nodes.
Utilized single-cell RNA sequencing and spatial transcriptomics to capture over 671,000 cells.
Conducted ligand-receptor interaction analyses to understand cancer cell and immune cell relationships.
Identified a subpopulation of cancer cells exhibiting enhanced oxidative phosphorylation linked to lymph node metastasis.
Found that elevated levels of the MOCCI protein correlated with worse patient prognosis.
Noted dysfunctional T follicular helper cells in metastatic lymph nodes, which impaired immune responses.

Abstract

Objective: 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. Methods: 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 ligandreceptor analyses were used to examine primary LN metastatic cancer cell (PLMC)immune interactions. Results: 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 nave 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. Conclusions: This study delineated transcriptional differences between primary tumors and MetLNs in lung cancer, thereby providing a foundation for further exploration of LN metastasis.

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Cite This Study

Zhang et al. (Thu,) studied this question.

synapsesocial.com/papers/699a9ca1482488d673cd260f https://doi.org/https://doi.org/10.20892/j.issn.2095-3941.2025.0587

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