A frozen human wound-repair reference reveals heterogeneous tumor niches and conditional immunotherapy associations
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Purpose
Tumors are often framed as unresolved wounds, but the extent to which independently defined physiological repair programs are recontextualized across cancers remains uncertain.
Methods
We derived five lineage-associated modules and a composite score from 58,823 cells in a longitudinal human skin-wound cohort before examining tumors. Frozen modules were evaluated in paired hepatocellular carcinoma and lung adenocarcinoma single-cell datasets, spatial and cell-resolved non-small-cell lung cancer cohorts, and four pretreatment immune-checkpoint-inhibitor cohorts. Patient- or section-level inference and prespecified sensitivity analyses were retained.
Results
Myeloid repair modules showed the most consistent tumor-associated increase in paired cancers; other lineage effects varied by context. Repair-high non-small-cell lung cancer regions combined epithelial/proliferative, extracellular-matrix fibroblast, and C1QC/broad-myeloid programs, whereas repair-cytotoxic neighborhood correlations were split across sections. In six Prime 5K Xenium patients, repair-high regions were fibroblast enriched (+0.239 high-minus-low fraction; 6/6 concordant; exact sign-flip P=0.031; FDR=0.047) and T/NK depleted (−0.151; 6/6; FDR=0.047). Direct ligand-receptor neighbor effects were not reproducible. Repair_FBI showed an adverse ICI-response direction, but the random-effects estimate was imprecise (OR=1.69, 95% CI 0.81-3.51).
Conclusion
Tumors reuse elements of physiological repair to form heterogeneous multicellular niches. Fibroblast remodeling is the most stable candidate; the evidence supports conditional association, not universal immune exclusion, a senescence-defined state, or a generalizable ICI biomarker.
