Fig. 6: LDHA expression, tumor biology, and therapeutic modulation.

A LDHA is significantly expressed in TP53-and BRCA-mutant tumors and more so in TP53-mutants. B Lactate accumulation is time-dependent in tumor cells and indicates increased glycolytic flux and LDHA activity. C LDHA-high tumors have a lower pH, which characterizes an acidic microenvironment that facilitates immune evasion and chemoresistance. D Lactate-mediated chromatin modification indicates epigenetic reprogramming (H3K18la) in LDHA-high tumors. LDHA may be related to multidrug resistance by introducing drug resistance genes (ABCB1, GSTP1, TOP2A) that are highly expressed in LDHA-high tumors. E shows upregulation of drug-resistance genes (ABCB1, GSTP1, TOP2A) in LDHA-high tumors compared with LDHA-low tumors, supporting the association between LDHA-high status and chemoresistance. F Low IFNG levels of LDHA-high tumors are indicative of suppressed anti-tumor immunity. G Higher resistance to the cisplatin in the LDHA high cells of ovarian cancer, which is demonstrated by higher IC50 values. H Additional immunological exhaustion is represented by higher levels of PD-1 on CD8 + T cells. I Immune-evasive phenotype of LDHA-high tumors is reinforced by high expression of checkpoint genes (PD-L1, IDO1). J FX11 therapy decreases the accumulation of lactate by means of inhibiting LDHA activity. K FX11 recovers cisplatin sensitivity and reduces IC50. L FX11 stimulates T cell activation of CD8+ cells, reversing immunosuppression. Collectively, the results indicate that LDHA is a mediator of metabolic reprogramming, chemoresistance, and immune evasion, whereas FX11 represents a therapeutic opportunity.