Lactate Reprograms Glioblastoma Immune Escape Through Histone Lactylation

Introduction: Glioblastoma (GBM), the most common and lethal primary brain cancer, can both evade anti-tumor immune responses and undergo metabolic reprogramming towards lactate production via the Warburg Effect. However, the relationship between GBM metabolism and immune evasion remains unclear. Recently, a novel role of lactate was first described, whereby lactate regulates gene expression through a histone modification termed histone lactylation. Here, we explore the previously uncharacterized function, regulation, and therapeutic vulnerabilities of histone lactylation in cancer.

Methods: To elucidate our findings, we leveraged in silico transcriptomic and single-cell datasets, performed RNA-seq and ChIP-seq, and utilized human patient-derived in vitro cultures and in vivo mouse GBM models.

Results: First, we observed that histone lactylation levels are elevated in GBM compared to non-tumor brain cells. Next, we discovered that lactate produced by GBM and microglia co-culture induced GBM epigenetic reprogramming via histone lactylation. This reprogramming led to the suppression of microglial phagocytosis by transcriptional upregulation of cluster of differentiation 47 (CD47), a “don’t eat me” signal, in GBM cells. Mechanistically, proteomics revealed that lactylated histone interacted with heterochromatin component chromobox protein homolog 3 (CBX3). To regulate histone lactyltransferase activity, CBX3 bound histone acetyltransferase P300 to induce P300 substrate selectivity toward lactyl-coA and promote a transcriptional shift toward an immunosuppressive phenotype. Genetic targeting of CBX3 increased microglial phagocytosis of GBM cells and reduced tumor growth in vivo. Concordantly, microglia depletion in vivo diminished the inhibitory effects of CBX3 knockdown, supporting the immunomodulatory role of CBX3. Leveraging these findings, pharmacologic targeting of lactate production augmented the efficacy of anti-CD47 immunotherapy by reducing tumor burden and prolonging survival in GBM mouse models.

Conclusion : These results demonstrate that tumor microenvironment-derived lactate mediates a metabolism-induced epigenetic reprogramming of GBMs that contributes to CD47-dependent immune evasion. Targeting this paradigm provides opportunities for clinically relevant immunotherapeutic interventions in glioblastomas and other brain tumors.