Table 3.
Therapeutic vulnerabilities and biomarker-guided stromal strategies in LSCC.
| Strategy | Mechanistic aim | Most relevant CAF-immune context | Development maturity | LSCC evidence status | Candidate biomarkers for selection |
|---|---|---|---|---|---|
| FAP-directed strategies | Selective depletion/targeting of activated fibroblasts | ecmCAF-high, FAP-rich fibrotic tumors | Early clinical/translational across cancers | Indirect to moderate | FAP, POSTN, COMP, collagen-rich stroma, C1QC/SPP1 macrophage proximity |
| NOX4 inhibition | CAF normalization; reversal of myofibroblastic activation | myCAF-high, fibrotic-excluded tumors | Strong preclinical; early clinical HNSCC signal | High translational relevance, not LSCC-specific clinically | αSMA, POSTN, FAP, low intratumoral CD8 |
| TGF-β blockade | Reduce matrix barrier, regulatory T-cell induction, myCAF maintenance | myCAF-dominant immune exclusion | Preclinical to early translational | Indirect but strong mechanistic support | TGF-β signature, collagen density, invasive-front fibrosis |
| CXCL12/CXCR4 antagonism | Release T-cell trapping; reduce myeloid-derived suppressor cell recruitment | iCAF-rich or stromally trapped T-cell lesions | Early clinical/translational | Indirect to moderate | CXCL12, CXCR4, stromal T-cell marginalization |
| IL-6/JAK/STAT3 inhibition | Block inflammatory myeloid skewing | iCAF-dominant, myeloid-rich tumors | Clinically available drugs; limited LSCC-specific biomarker data | Indirect | IL-6, pSTAT3, CD163/CD206 myeloid enrichment |
| Stromal checkpoint targeting | Reverse stromal checkpoint-like suppression | Checkpoint-active stromal tumors | PD-1/PD-L1 clinically established; Gal9 early-stage | PD-L1 partially direct; Gal9 indirect in LSCC | Stromal PD-L1, Gal9, exhausted CD8 phenotype |
| Extracellular matrix/mechanical niche targeting | Reduce stiffness and mechanosignaling | ecmCAF/myCAF-rich invasive-front disease | Preclinical/translational | Indirect | collagen density/alignment, LOX/LOXL2, POSTN/COMP, ITGA6-related tumor-matrix signaling, cartilage-adjacent fibrosis |
| Extracellular vesicle/RNA-targeted strategies | Interrupt fibroblast-derived extracellular vesicle cargo and non-coding RNA signaling | Stemness-associated, residual, or plastic tumors | Early preclinical | Direct LSCC biological basis but not clinically mature | CAF-derived extracellular vesicle microRNA profile, exploratory RNA markers |