2026-07-25

Review Framework: The Microbiome–Lactate–Lactylation Axis in Tumor Biology

I. Introduction

Cancer as a disease of both genetic mutations and microenvironmental dysregulation — metabolic and microbial ecosystems as emerging pillars of tumor biology
Historical perspective: from Warburg effect (1920s) to histone lactylation discovery (2019) — the conceptual journey from metabolic waste to signaling hub to epigenetic modification
The gut microbiome as an active modulator of host metabolism, immunity, and therapeutic response — beyond correlation to causation
The convergence of three rapidly evolving fields: tumor metabolism (lactate), epigenetics (lactylation), and microbiology (tumor-resident & gut microbiota)
Scope of this review: systematically dissect the microbiome–lactate–lactylation axis and its therapeutic implications in gastrointestinal cancers

Warburg effect and aerobic glycolysis: metabolic reprogramming as a hallmark of cancer
The lactate shuttle hypothesis: intercellular and inter-organ lactate trafficking via MCT1/MCT4 transporters
Lactate as a signaling molecule: GPR81/HCAR1 receptor activation and downstream cascades (NF-κB, HIF-1α)
Immunosuppressive functions of lactate: M2 macrophage polarization, CD8+ T cell inhibition, Treg metabolic support, dendritic cell suppression
The reverse Warburg effect: CAF–tumor cell metabolic symbiosis driving EMT and metastasis
Lactate in the acidic TME: pH-dependent immune evasion and chronic inflammation

Discovery of Kla (2019): lysine lactylation as a novel histone post-translational modification
Biochemical basis: lactyl-CoA as the acyl donor; “lactate clock” — slow kinetics coupling sustained stress to persistent gene expression
Writers of lactylation: p300/CBP as histone lactyltransferases; AARS1/AARS2 as non-canonical lactyltransferases
Erasers of lactylation: HDAC1–3 (strong delactylase activity) and SIRT1–3 (weak activity); SIRT3 as site-specific eraser (H3K9la, cyclin E2)
Functional landscape of Kla in cancer: histone Kla (H3K18la in promoter activation), non-histone Kla (HMGB1, METTL16, MRE11), and downstream consequences (autophagy, immune evasion, DNA repair)
Lactylation-driven therapy resistance: docetaxel resistance in prostate cancer via CNN1-mediated autophagy; B7-H3 upregulation and immune evasion
Kla in GI cancers: comprehensive roles spanning metabolic enzyme modification, transcriptional reprogramming, and myeloid cell polarization

Gut microbiome-mediated carcinogenesis: genotoxicity (colibactin, BFT), inflammatory injury (TLR/MyD88/NF-κB), and epigenetic remodeling (SCFAs, folate)
Dysbiosis as a permissive state: loss of protective symbionts combined with pathobiont expansion lowering the threshold for malignant transformation
Tumor-resident microbiota: presence across multiple cancer types; active modulation of oncogenic signaling, gene mutations, and immune microenvironment
The passenger-to-driver paradigm shift: intratumoral bacteria persist in metastases and regulate therapeutic response
Key bacterial players: Fusobacterium nucleatum in CRC, E. coli in CRLM, Helicobacter pylori in gastric cancer
Microbial metabolites in cancer: butyrate (HDAC inhibition, anti-inflammatory), secondary bile acids (DNA damage, pro-carcinogenic), TMAO, inosine, indole derivatives

Bidirectional regulation: gut microbiota as both source and modulator of systemic and intratumoral lactate
The E. coli–lactate–RIG-I lactylation axis: tumor-resident E. coli drives glycolysis → lactate production → p300-mediated RIG-I K852 lactylation → MAVS disruption → NF-κB suppression → NLRP3 downregulation → M2 polarization → Treg expansion → immune evasion
Small-molecule RIG-I lactylation inhibitors: proof-of-concept for therapeutically targeting the microbiota–lactylation interface
Microbial metabolite antagonism of lactylation: butyrate-mediated HDAC inhibition counteracting lactate-driven epigenetic reprogramming
TLR-MyD88-BCAP signaling: bacterial products driving host glycolytic lactate production
Symbiotic and competitive dynamics: lactate-producing bacteria (Lactobacillus, Bifidobacterium) vs. butyrate-producing bacteria (Faecalibacterium, Roseburia) in shaping the TME
L/D-lactate stereoisomers: differential immunological and bacteriological effects — an underexplored dimension

Lactate metabolism inhibitors: MCT1/MCT4 inhibitors (blocking lactate transport), LDHA inhibitors (blocking lactate synthesis) — limited monotherapy efficacy, greater value as combination partners with ICB or chemotherapy
Epigenetic lactylation modulators: p300 inhibitors (blocking Kla deposition), HDAC inhibitors (context-dependent effects on both acetylation and lactylation), SIRT activators
Microbiome-targeted interventions — global approaches: fecal microbiota transplantation (FMT), dietary fiber supplementation to promote SCFA-producing bacteria
Microbiome-targeted interventions — precision approaches: engineered probiotic consortia, bacteriophage-guided microbiota editing, selective bacterial enzyme inhibition
Nanoplatforms for microbiota modulation: targeted delivery systems enabling spatiotemporal control of microbial interventions within the TME
Combination strategies: integrating lactate/lactylation inhibitors with microbiome modulation and conventional immunotherapy/chemotherapy

The microbiome–lactate–lactylation axis represents a unified framework linking microbial ecology, tumor metabolism, and epigenetic gene regulation
Gut and intratumoral microbiota function as upstream regulators of the lactylation cascade, suggesting that microbiome-targeted interventions may bypass the need to directly target epigenetic enzymes
Lactylation eraser enzymes (HDAC1–3, SIRT1–3) and writers (p300, AARS1/2) constitute a druggable epigenetic interface with therapeutic potential
Critical knowledge gaps remain: relative contribution of microbial vs. host-derived lactate, site-specific lactylation functional mapping, and L/D-lactate isomer-specific effects

Systematic characterization of the tumor-resident microbiota composition across different cancer types and metastatic sites
Elucidating the stoichiometry and spatial compartmentalization of microbial vs. host lactate contribution to the lactylome
High-resolution lactylomic profiling at single-cell and spatial resolution to map cell-type-specific Kla landscapes
Development of isoform-selective lactylation inhibitors with minimal off-target effects on acetyl-CoA metabolism
Clinical validation of microbiome modulation (FMT, defined consortia, phage therapy) as adjuvants to immunotherapy in prospective trials
Engineering synthetic biology tools (sense-and-respond probiotics, in situ lactate-consuming bacteria) for TME remodeling
Investigating the role of D-lactate (exclusively microbial origin) as a biomarker and functional mediator distinct from L-lactate
Longitudinal multi-omics integration (metagenomics, metabolomics, lactylomics) to establish causality in the microbiota–lactate–lactylation axis