Letter to the Editor: Decoding intrahepatic cholangiocarcinoma through lactate metabolism - from cellular states to therapeutic targets

Abstract

Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive liver cancer characterized by significant intratumoral heterogeneity and limited treatment options. In the recent issue of World Journal of Gastroenterology, Wu et al revealed that lactate metabolism (LM) is a key determinant of malignant cell states in ICC, extending beyond its traditional role as a metabolic byproduct. Distinct tumor subpopulations exhibit a gradient of lactate metabolic activity, defining a hierarchy linked to differentiation, plasticity, and clinical aggressiveness. High LM states correlate with stemness features, enhanced mitochondrial function, and immunosuppressive interactions within the tumor microenvironment. Mitochondrial regulators such as cytochrome c1 connect lactate utilization to oxidative phosphorylation and redox homeostasis. Deciphering ICC through LM provides a unifying framework for tumor stratification and reveals potential metabolic-immune therapeutic targets.

Key Words: Intrahepatic cholangiocarcinoma; Lactate metabolism; Tumor heterogeneity; Single-cell transcriptomics; Tumor microenvironment; Metabolic reprogramming

Core Tip: Lactate metabolism organises intrahepatic cholangiocarcinoma heterogeneity, linking metabolic activity to cellular hierarchy, mitochondrial function, and immune evasion, offering new avenues for stratification and therapy.

TO THE EDITOR

Cholangiocarcinoma (CCA) is an aggressive adenocarcinoma and the second most common primary liver cancer after hepatocellular carcinoma, accounting for approximately 3% of gastrointestinal malignancies and 15% of primary liver tumors[1,2]. Intrahepatic CCA (ICC), arising within the liver, is among the deadliest primary liver cancers, with a poor long-term prognosis and a globally rising incidence. Despite advances in molecular profiling, targeted therapies, and immunotherapy, clinical outcomes remain suboptimal. A major contributing factor is the profound intratumoral heterogeneity of ICC, which complicates diagnosis, biomarker reliability, and therapeutic efficacy[3]. Understanding the biological principles that govern this heterogeneity is therefore critical for improving ICC management.

In this context, the work by Wu et al[4] published in the recent issue of World Journal of Gastroenterology provides compelling evidence that lactate metabolism (LM) serves as a previously overlooked organizing axis of ICC biology. By integrating single-cell transcriptomics, bulk RNA sequencing, and machine learning, the authors reposition lactate from a metabolic byproduct to a functional determinant of malignant cell state, tumor hierarchy, and aggressiveness[4]. This perspective reframes our understanding of ICC development and microenvironmental remodeling.

From metabolic byproduct to tumor-defining force

While metabolic reprogramming is a cancer hallmark, lactate production has often been viewed merely as an epiphenomenon of aerobic glycolysis. Growing evidence, however, establishes lactate as a bioactive metabolite influencing gene expression, redox balance, intercellular communication, and immune responses. In ICC, bulk analyses have implicated lactate in protein lactylation, immune suppression, and therapy resistance, though such approaches mask cellular heterogeneity[5].

Wu et al[4] overcome this limitation by systematically profiling LM activity at single-cell resolution. Their analysis reveals that LM activity is not uniform but defines distinct metabolic states within the tumor. By classifying malignant epithelial cells into high-, intermediate-, and low-LM subpopulations, they demonstrate that metabolic status correlates with transcriptional programs, differentiation trajectories, and malignant potential. This introduces the concept of “lactate-defined tumor states”, suggesting LM activity as a biological classifier in ICC[4].

LM and tumor hierarchy

A key finding is the strong correlation between LM activity and cellular differentiation. Malignant cells with high LM activity exhibit elevated CytoTRACE scores, indicating a more plastic, less differentiated phenotype. Pseudotime analysis further positions these cells at the beginning of the malignant trajectory, with intermediate- and low-LM cells representing more differentiated downstream states[6].

This hierarchical organization implies that LM activity is closely tied to metabolic stemness—a concept increasingly recognized across cancer types. Enhanced LM appears to confer evolutionary advantages, such as greater adaptability to hypoxia, nutrient scarcity, and therapeutic stress, rather than being a passive consequence of proliferation. Thus, ICC heterogeneity can be viewed not only as a genetic mosaic but as a metabolically stratified ecosystem where lactate-rich states drive tumor progression[7].

Cytochrome C1 as a nexus of metabolism and mitochondria

Using an integrative machine-learning framework, Wu et al[4] identified twelve LM-associated genes, with cytochrome C1 (CYC1) emerging as a prominent driver of LM activity and malignant behavior. CYC1 is a core component of mitochondrial complex III, placing it at the intersection of oxidative phosphorylation, redox regulation, and metabolic flux. This finding challenges the traditional glycolysis vs mitochondrial respiration dichotomy. High-LM activity cells are enriched not only for glycolytic pathways but also for oxidative phosphorylation and mitochondrial translation, supporting the existence of hybrid metabolic phenotypes. In such cells, lactate may serve as both a glycolytic end-product and a mitochondrial fuel, maintaining bioenergetic flexibility[8].

The study functionally validates CYC1, demonstrating that its knockdown significantly suppresses ICC cell proliferation, migration, and invasion. This establishes a causal link between mitochondrial function and lactate-driven malignancy, positioning CYC1 as a metabolic gatekeeper that couples mitochondrial respiration with LM to promote aggressive tumour behaviour[4].

Lactate as a mediator of tumor–microenvironment crosstalk

Beyond intrinsic tumour cell biology, this work highlights LM’s role in shaping the tumour microenvironment. Intercellular communication analysis reveals that high-LM malignant cells engage in more extensive signalling interactions, particularly through pathways involving macrophage migration inhibitory factor and midkine. These molecules are known to regulate immune suppression, angiogenesis, and stromal activation, linking metabolic reprogramming to microenvironmental remodelling[4].

Lactate accumulation has well-documented immunosuppressive effects, including inhibition of cytotoxic T-cell and natural killer cell function and polarization of macrophages toward pro-tumor phenotypes. By connecting LM activity to specific ligand–receptor networks, Wu et al[4] provide mechanistic insight into how metabolic states may orchestrate immune evasion in ICC, reinforcing lactate’s role as a signaling molecule integrating metabolism and immunity[9].

Clinical and therapeutic implications

First, LM-based stratification may offer a novel framework for risk assessment and prognosis in ICC. The identified LM-related gene signature, particularly CYC1, could complement existing molecular classifiers by capturing dynamic metabolic states rather than static genetic alterations.

Second, targeting lactate production, transport, or utilization—potentially in combination with mitochondrial modulators—may selectively disrupt aggressive, high-LM tumor states. Given the link between LM and immune suppression, combining metabolic interventions with immune checkpoint blockade represents a promising therapeutic strategy for metabolically active ICC subtypes.

In ICC, LM biomarkers demonstrate clear prognostic value, though evidence for predicting treatment response remains primarily mechanistic. Key biomarkers include lactate dehydrogenase-A (LDHA), and a six-gene LM-related signature (LDHA, ETHE1, ATAD3A, SLC25A19, SLC13A5, LARS2) that stratifies patients into high- and low-risk groups. This signature acts as an independent prognostic factor with moderate predictive accuracy[10,11].

Mechanistic studies suggest therapeutic potential; for example, LDHA knockdown suppresses tumor growth in immunocompetent mice and inhibits migration and proliferation in vitro via ERK signaling and reactive oxygen species-mediated apoptosis. These findings support LDHA as a potential target and have informed the development of clinical nomograms combining LM scores with TNM staging for patient stratification[12]. However, clinical data on treatment response relative to biomarker status are lacking, highlighting the need for prospective trials to validate the predictive utility of LM biomarkers in guiding specific therapies.

One of the important limitations is that the metabolic activity is inferred from gene expression and not directly measured, and that spatial or metabolic flux validation in ICC is still lacking.

Conclusion

Wu et al[4] compellingly demonstrate that LM is a central architect of ICC biology, organizing tumor hierarchy, mitochondrial function, and immune interactions. By linking metabolic activity to malignant cell state and clinical outcome, this work shifts the conceptual framework of ICC from purely genetic heterogeneity toward metabolic identity. Targeting this metabolic architecture may open new avenues for precision therapy in a disease that has long resisted effective treatment.