Targeting lysine acetyltransferase 6A/B in cancer: a conceptual and translational review of epigenetic regulation, immune microenvironment remodeling, and the dual-compartment hypothesis.

While lysine acetyltransferase 6A (KAT6A; MOZ/MYST3) and 6B (KAT6B; MORF/MYST4) function as context-dependent oncogenic drivers-with KAT6B also displaying tissue-specific tumor-suppressive roles-their pharmacological targeting holds promise as a therapeutic avenue. This conceptual and translational review synthesizes evidence from genetic depletion models, pharmacological catalytic inhibitors, and emerging proteolysis-targeting chimera (PROTAC) degraders, introducing the "Dual-Compartment Hypothesis" as a conceptual interpretive framework to organize current evidence and generate testable hypotheses regarding their putative impacts on the tumor immune microenvironment (TIME). Under this framework, KAT6A/B blockade within the primary tumor compartment is proposed to indirectly foster regional antitumor immunity via preclinically implicated pathways, including tumor cell ferroptosis, cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) activation, and interleukin-6 (IL-6) suppression, alongside putative downstream influences on immune checkpoints. In contrast, systemic drug exposure in the secondary compartment may directly alter hematopoiesis and lymphocyte development, creating a tension between local immune activation and systemic constraints. Importantly, immune cells within the tumor microenvironment may also be directly suppressed by KAT6A/B inhibition-an alternative outcome that remains to be systematically investigated. Resolving these divergent outcomes necessitates distinguishing genetic knockout/knockdown (KO/KD) from pharmacological inhibition or degradation-a distinction that is critical because much of the mechanistic evidence derives from genetic models, while accounting for KAT6A versus KAT6B isoform selectivity. Finally, we outline testable translational frameworks, such as intermittent dosing schedules and rational immunotherapeutic combinations, to direct subsequent experimental and clinical validation, while acknowledging that current early-phase clinical observations (objective response rate [ORR]/clinical benefit rate [CBR]) reflect composite therapeutic responses and require further paired biomarker validation to definitively isolate immune-mediated effects.