Table 2.

Provisional evidence-stratified CAF framework in LSCC.

CAF program	Hallmark markers/pathways	Dominant biological functions	Putative spatial niche	Evidence strength in LSCC	Key translational implication
myCAF	ACTA2, TAGLN, POSTN, MMP11, COL1A1; TGF-β signaling	Extracellular matrix deposition, tissue stiffening, CD8+ T-cell exclusion, therapy resistance	Invasive front, fibrotic stroma, perivascular zones	Moderate direct + strong translatable	Strong rationale for NOX4 and TGF-β-directed normalization
iCAF	IL6, IL8, CXCL1, CXCL5, CXCL12; inflammatory secretome	Myeloid skewing, cytokine amplification, T-cell trapping, inflammatory remodeling	Immune-interacting stromal niches, perivascular regions	Limited-to-moderate direct + strong translatable	Supports IL-6/JAK/STAT3 and CXCL12/CXCR4 targeting
apCAF	MHC-II, CD74, antigen-processing genes	Context-dependent antigen presentation, potential regulatory T-cell induction	Immune-enriched stromal compartments	Indirect/weakly validated	Requires direct LSCC validation before therapeutic use
ecmCAF	FAP, COL11A1, POSTN, COMP, FN1, MMPs, LOX/LOXL2, fibrillar collagen programs	Matrix deposition, degradation, fiber alignment, collagen crosslinking, integrin/mechanosignaling, invasion, immune exclusion, lymphovascular niche conditioning	Invasive front, cartilage interface, perivascular and lymphovascular regions, metastatic nodal stroma	Moderate direct/adjacent + strong translatable	Candidate state for FAP-directed, ECM-targeted, and macrophage-interaction-targeted strategies
Putative immune-trapping CAF	MHC-I-high, CXCL9/10/12, LGALS9	Functional CD8+ T-cell suppression, immune trapping, checkpoint-like stromal signaling	Immune-excluded stromal regions	Hypothesis-generating in LSCC; strong HNSCC support	High-priority validation target for stromal checkpoint combinations