Targeting the KMT2D-driven Enhancer-Immune-Metabolic axis in HNSCC: Reconciling the paradox for precision therapy

Head and neck squamous cell carcinoma (HNSCC) carries a substantial mortality burden, driven largely by locoregional recurrence. Although immune checkpoint blockade (ICB) is now standard-of-care for recurrent/metastatic disease, primary resistance and limited durability remain major barriers. Clinical outcomes are not determined by PD-L1 status alone, but instead emerge from a multidimensional tumor ecosystem shaped by genomic alterations and epigenetic-metabolic reprogramming. KMT2D (MLL4), a frequently mutated histone methyltransferase in HNSCC, exemplifies this complexity: it is traditionally regarded as a differentiation-preserving tumor suppressor, yet accumulating data suggest context-dependent roles in sustaining oncogenic stemness and metabolic fitness.

This review reconciles these seemingly discordant observations through an "Enhancer-Immune-Metabolic Framework," positioning KMT2D as an epigenetic rheostat rather than a binary determinant. We synthesize evidence that KMT2D alteration rewires enhancer landscapes, with particular emphasis on the PER2 axis, to promote a shift toward aerobic glycolysis. We further discuss how this metabolic state can potentiate immune exclusion by dampening antigen presentation programs and by supporting an immunosuppressive myeloid milieu. A central mechanistic link highlighted here is histone lactylation (e.g., H3K18la), proposed to couple glycolytic flux to chromatin remodeling and transcriptional outputs that favor immune evasion. Building on these concepts, we outline translationally actionable vulnerabilities in KMT2D-altered tumors, including: (i) synthetic lethal strategies with PARP inhibitors, (ii) metabolic blockade to disrupt glycolysis-associated immune suppression, and (iii) epigenetic "priming" approaches to re-open enhancers governing antigen presentation and T cell-inflamed states, thereby enhancing ICB responsiveness.

KMT2D-driven enhancer remodeling provides a unifying lens to connect metabolic reprogramming with immune escape in HNSCC. Conceptualizing KMT2D as an epigenetic rheostat supports biomarker-informed combination strategies-integrating DNA damage repair targeting, metabolic interventions, and epigenetic priming-to overcome ICB resistance and improve durable disease control in KMT2D-altered HNSCC.