In recent, modulation of epigenetic writer enzymes such as HATs are implicated in the inflammatory landscape of tumor microenvironment specifically in the context of polarization of M1 macrophage to M2 macrophage . Among various HATs, the enzymatic role of HAT p300 to alter the acetylation mark on histone and other tumor suppressors is highlighted But the relevance of HAT p300 in contributing lactylation marks on histone and other proteins using lactyl-CoA as a substrate remains obscure. The possibility of metabolic strategies by cancer cells to use lactylation as a part of mitigating acetylation marks on histone proteins could be explored. This would be almost similar to shunting off HATs by cancer and cancer-associated cells as a part of the activation of oncoproteins during chromatin remodeling to achieve protumor attributes. In recent, non-histone proteins such as PKM2 and beta-catenin are suggested as protein targets that modulate the macrophage phenotype transition in cancer and other human disease conditions . The relevance of HAT p300 in modulating the transcriptional landscape of cancer cells and tumor-associated immune cells such as macrophages is considered as a link between the metabolic-epigenomic axis that may use metabolites such as acetyl-CoA and lactyl-CoA In a direction to the unresolved question of the nature of substrate and enzymes in lactylation, there is a hint of the potential enzymatic role by HAT p300 . Among various HATs, HAT p300 is suggested to modulate the transcription of genes that are linked to the development of various human diseases including cancer and immune-related diseases that involve macrophages in their tissue environment . HAT p300 is determined to comprise several domains including HAT domain (1285-1664) amino acid residues . HAT p300 catalytic domain is antagonized by various small molecules including A-485, I-CBP112, natural products, and bi-substrate analogs (Lys-CoA) . However, binding affinity and position by lactyl-CoA to p300 HAT is not known and may be potentially linked with the lactylation process. Although the active site on HAT p300 is reported in earlier works by showing key amino acid residues such as PHE1374, LEU1398, SER1400, ARG1410, THR1411, TYR1414, HIS1415, ARG1312, GLU1423, LYS1426, LYS1427, GLU1477, and ARG1478 .