Lactic acid (LA) has transitioned from being perceived as a mere glycolytic waste product to a pivotal regulator of tumor–immune crosstalk. Historical milestones—from Scheele’s 1780 isolation from sour milk to Zhao’s 2019 discovery of histone lactylation—reveal an expanding biochemical repertoire that now encompasses pH control, G-protein-coupled receptor (GPR81/132) signaling, post-translational modification via lysine lactylation, and multi-directional metabolic shuttling between cytoplasm, mitochondria, and neighboring cells. Within the tumor microenvironment (TME), high glycolytic flux exports lactate and protons through monocarboxylate transporter 4 (MCT4), acidifying the extracellular milieu to ~6.5–6.8. This acidity degrades extracellular matrix, blunts drug uptake, and, via protonation, neutralizes weak-base chemotherapeutics. Cancer cells exploit the same molecule as fuel: MCT1-mediated uptake drives tricarboxylic acid cycle oxidation, NADPH generation via IDH1, and lactylation of DNA-repair proteins NBS1 and MRE11, enhancing genomic stability and chemoresistance. Concurrently, GPR81-cAMP-PKA-TAZ/TEAD signaling elevates PD-L1 expression, facilitating immune escape.

HOXB13, a B-class homeobox transcription factor, sits at the hub of developmental gene networks yet has emerged as a double-edged sword in human cancer. While indispensable for embryonic patterning and androgen-dependent organogenesis, its expression is frequently hijacked or extinguished by epigenetic, mutational and post-translational events that drive tumour initiation, progression and therapy resistance. Across more than twenty malignancies, the protein acts as either oncogene or tumour suppressor, depending on tissue context, interacting partners and mutational status.