SLC16A3 links tumor metabolism to therapeutic opportunities in hepatocellular carcinoma
Review Article

SLC16A3 links tumor metabolism to therapeutic opportunities in hepatocellular carcinoma

Zhiyan Li1,2, Zeyu Zhou1,2, Shuwei Liang1,2, Hao Liu1,2, Qiyu Sun1,2, Jian Li1,2

1Department of Clinical Laboratory, Affiliated Hospital of Chengde Medical College, Chengde, China; 2Hebei Key Laboratory of Panvascular Diseases, Chengde, China

Contributions: (I) Conception and design: Z Li, J Li, Q Sun; (II) Administrative support: J Li, Q Sun; (III) Provision of study materials or patients: H Liu; (IV) Collection and assembly of data: Z Zhou, S Liang; (V) Data analysis and interpretation: Z Li, Z Zhou; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Jian Li, PhD. Department of Clinical Laboratory, Affiliated Hospital of Chengde Medical University, No. 36 Nanyingzi Street, Shuangqiao District, Chengde 067000, China; Hebei Key Laboratory of Panvascular Diseases, Chengde, China. Email: chengdeli79@cdmc.edu.cn.

Abstract: Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, remains one of the most common and lethal malignancies worldwide. Despite advances in diagnostic techniques and therapeutic approaches, the prognosis of patients with advanced HCC is still poor because of high rates of recurrence, metastasis, and therapeutic resistance. Increasing evidence indicates that metabolic reprogramming is a hallmark of HCC progression and plays a critical role in shaping the tumor microenvironment. Among the key regulators of tumor metabolism, solute carrier family 16 member 3 (SLC16A3), also known as monocarboxylate transporter 4 (MCT4), has attracted considerable attention. SLC16A3 is frequently overexpressed in a variety of human cancers, and its elevated expression has been consistently associated with aggressive tumor behavior and unfavorable clinical outcomes. In this review, we comprehensively summarize the current evidence regarding the biological functions of SLC16A3 in cancer, with particular emphasis on its contribution to HCC progression. We discuss the molecular mechanisms and signaling pathways through which SLC16A3 regulates tumor metabolism, proliferation, invasion, metastasis, immune modulation, and resistance to therapy. We also highlight the clinical significance of SLC16A3 as a prognostic biomarker and a potential therapeutic target. Collectively, these findings provide a broader understanding of the role of SLC16A3 in HCC and offer valuable perspectives for the development of more effective targeted therapeutic strategies to improve patient outcomes.

Keywords: SLC16A3; hepatocellular carcinoma (HCC); immune infiltration; therapeutic target; metabolic reprogramming

Submitted Apr 01, 2026. Accepted for publication Jun 03, 2026. Published online Jun 24, 2026.

doi: 10.21037/tcr-2026-0772

Introduction

Hepatocellular carcinoma (HCC) is recognized as the sixth most common malignancy worldwide and the third leading cause of cancer-related mortality. Alarmingly, the incidence of HCC in China is as high as 9%, while the mortality rate reaches 13%, ranking among the highest nationwide (1). Due to its insidious onset, many patients are diagnosed at advanced stages with highly aggressive disease. Even after curative treatments, the risk of recurrence remains high, and the overall 5-year survival rate is only 18% (2). Although current therapeutic strategies extend beyond surgical resection to include ablation, transarterial chemoembolization (TACE), and radiotherapy, their overall efficacy remains unsatisfactory (3).

With the deepening of cancer biology research, lactate has gained increasing attention for its pivotal role in tumor progression. Lactate is a key product of glycolysis and a metabolic regulator linking multiple cancer hallmarks, including sustained angiogenesis, immune evasion, and energy metabolic reprogramming (4). Consequently, investigating lactate transporters offers new opportunities and strategies for cancer therapy (5-8).

Lactate is primarily produced via glycolysis, particularly under hypoxic conditions or during intense exercise, as a critical energy metabolism marker. Under normal physiological conditions, pyruvate typically enters the tricarboxylic acid (TCA) cycle within mitochondria, except during hypoxia, where it is converted to lactate to sustain cellular energy supply (9). In contrast, tumor cells exhibit a distinct metabolic phenotype by preferentially performing glycolysis even in sufficient oxygen. This phenomenon, first described in the 1920s by Otto Warburg and termed the “Warburg effect” (10,11), enables cancer cells to utilize lactate not only as an energy substrate but also as a signaling molecule that influences surrounding cells, induces metabolic reprogramming, stimulates angiogenesis, and triggers inflammatory responses. Thus, lactate functions not merely as a metabolic byproduct but also as a crucial mediator of intercellular communication within the tumor microenvironment (TME) (12,13).

SLC16A3, also known as monocarboxylate transporter 4 (MCT4), is one of the 14 members of the SLC16 gene family with important biological functions (14). Located on chromosome 2, SLC16A3 encodes a transmembrane protein primarily responsible for transporting lactate and other small monocarboxylates. Emerging evidence indicates that SLC16A3 expression is markedly upregulated in various cancers, particularly in HCC (15), which strongly correlates with tumor aggressiveness, stage, and prognosis. Furthermore, high expression of SLC16A3 has been linked to hypoxia in the TME, increased proliferative capacity, and enhanced invasive potential, suggesting a pivotal role in metabolic reprogramming and immune evasion. Functionally, SLC16A3 is localized to the plasma membrane and co-transports lactate with protons, thereby facilitating the efficient efflux of lactate produced in glycolytic tumor cells (16,17). Recent studies further demonstrate that elevated SLC16A3 expression in most malignancies is associated with poor prognosis (18-20). This review summarizes the complex interplay between SLC16A3 and tumor biology, focusing on its mechanistic roles in HCC progression and the potential of targeting SLC16A3 for therapeutic intervention (21).

The role of SLC16A3 in cancer

Tumor cells preferentially adopt aerobic glycolysis as their main metabolic pathway, even under oxygen-rich conditions—a hallmark of the Warburg effect. This reprogramming leads to excessive glucose consumption and substantial lactate production, rather than complete glucose oxidation through the TCA cycle (22). Consequently, lactate undergoes a fundamental shift in biological function, transforming from a mere metabolic waste product into a multifaceted regulator of tumor progression.

Lactate serves as an alternative energy substrate that can be reutilized by tumor cells and acts as a signaling molecule, activating oncogenic pathways through specific receptors such as GPR81. More importantly, lactate has recently been identified as a novel epigenetic regulator, mediating protein lactylation, including histone and non-histone modifications. These modifications directly influence gene expression, promoting tumor cell proliferation, immune escape, and therapeutic resistance (23).

Within this complex metabolic network, SLC16A3/MCT4 plays a central role as the primary “transporter”. Highly expressed in tumor cells, SLC16A3 is responsible for exporting intracellular lactate into the TME (24). This process relies on a precise proton-coupled transport mechanism: specific amino acid residues capture protons to open the channel, enabling lactate efflux, which is ultimately driven by electrochemical gradients. Such efficient lactate export maintains intracellular pH homeostasis, sustains high glycolytic flux, and acidifies the TME. This acidic milieu suppresses effector immune cells, such as CD8+ T cells and NK cells, while facilitating the infiltration of immunosuppressive cells, thereby promoting immune evasion and malignant progression (Figure 1).

Figure 1 Mechanistic diagram of SLC16A3 in tumor metabolic reprogramming and tumor microenvironment modulation.

Consistent with these findings, SLC16A3 is significantly overexpressed in multiple malignancies, including glioblastoma and lung adenocarcinoma. Its expression is closely associated with poor prognosis, chemoresistance, and dysregulated protein lactylation (e.g., p53 lactylation, which impairs its tumor suppressor function). Accordingly, targeting SLC16A3 directly (e.g., with natural compounds such as silibinin that inhibit MCT4 function) or indirectly modulating lactate metabolism (e.g., via LDH inhibitors such as stiripentol) represents an emerging strategy to enhance chemosensitivity and overcome resistance in cancer therapy (25,26).

SLC16A3, also known as MCT4, is a highly expressed transporter in tumor cells that plays a critical role in metabolic reprogramming and the tumor immune microenvironment. Structurally, SLC16A3 consists of 12 transmembrane helices forming a hydrated transport channel that selectively binds and transports lactate and other monocarboxylates. Its transport activity is proton-dependent, with lactate efflux coupled to proton co-transport, an essential mechanism for energy metabolism.

In malignant tumors, the overexpression of SLC16A3 leads to increased extracellular lactate accumulation, resulting in an acidic intracellular environment that promotes cancer cell proliferation and migration (27). Inhibition of SLC16A3 has been shown to reverse hypoxia-induced phenotypes and suppress tumor aggressiveness, highlighting its potential as a therapeutic target. The primary function of SLC16A3 is to export lactate from the intracellular to the extracellular space, thereby sustaining the high glycolytic state of cancer cells. By acidifying the TME through lactate efflux, SLC16A3 enhances tumor invasion and migration and impairs immune cell function, driving immunosuppression and immune evasion (28).

Clinical studies have demonstrated that high SLC16A3 expression is associated with poor prognosis. In lung cancer, for example, elevated SLC16A3 expression correlates with the presence of immunosuppressive cells, the expression of immune checkpoint molecules, and the release of inhibitory cytokines, collectively shaping an immunosuppressive TME and diminishing the efficacy of immunotherapy. Tao et al. further reported that SLC16A3 expression is closely associated with IL-8, potentially inducing immune tolerance in the microenvironment, affecting immunotherapy response, and ultimately influencing patient survival and prognosis. In addition to lung cancer, SLC16A3 has also been implicated in the malignant progression of breast, bladder, and colorectal cancers (Table 1).

Table 1

Roles of SLC16A3 in various cancers

Cancer type Authors Year SLC16A3 expression pattern Significance Reference
Lung cancer Tao Q, et al. 2022 HIF-1a-IL8 axis Prognosis, novel therapeutic target (29)
Xue L, et al. 2021 Immune cell infiltration, TMB Biomarker (30)
Zhang J, et al. 2024 Immune, TME Overall survival, prognosis (31)
Meng H, et al. 2022 Effects on zinc-lung cancer association Lung cancer risk, diagnostic (32)
Xu Z, et al.; Zhang L, et al. 2021; 2019 Glycolysis-related gene Overall survival, target treatment (33,34)
Ke H, et al. 2020 – Prognosis, diagnosis (35)
Ren W, et al. 2022 LCIIAR/hsa-miR-184/SLC16A3/CDCP1 prognostic and diagnostic biomarker (36)
Han L, et al. 2024 Central carbon metabolism Target treatment (37)
Renal cancer Fisel P, et al. 2013; 2015 Promoter DNA methylation Prognosis, diagnosis (38,39)
Gerlinger M, et al. 2012 Reverse the Warburg effect Metabolic target (40)
Bladder cancer Li C, et al. 2025 Glycolysis, m6A modification,
immune infiltration		 New target, predicting drug sensitivity, prognostic predictor, biomarker (41)
Zhao Y, et al. 2021 – Independent prognostic factor, overall survival (42)
Ord JJ, et al. 2005 Hypoxia-regulated Biomarker, target treatment (43)
Cervical cancer Yang X, et al. 2023 Warburg Overall survival, prognosis (44)
You S, et al. 2023 Glycolysis and redox pathways Overall survival, target treatment (45)
Priego-Hernández, et al. 2022 Metabolic reprogramming Overall survival, prognostic biomarkers (46)
Breast cancer Mewani RR, et al. 2006 Raf-1 related signaling pathways Overall survival, target treatment (47)
Pancreatic cancer Ren LK, et al. 2024 Viral carcinogenesis and protein process Prognosis, overall survival, target treatment (48)
Lee SH, et al. 2021 MAPK pathway, RAS signa, EMT Potential biomarker (49)
Yu S, et al. 2020 Cancer associated fibroblasts Overall survival, prognosis (50)
Prostate cancer cells De Wet L, et al. 2022 Sox2 gene target Prognosis, overall survival, target treatment (51)
Xie W, et al. 2021 IL-17 signaling pathway, Glycolysis Prognosis, overall survival, target treatment (52)
Vaz CV, et al. 2016 Glycolytic flux – (53)
Colon cancer Choi SH, et al. 2019 Hypoxic Rela/p65-ZBTB-FBI-1-HIF Target treatment, biomarker (54)
Wang J, et al. 2022 Immunosuppressive roles Metastasis, survival prognosis (55)
Zhou X, et al. 2024 Hsa_circ_0008621- miR-532-5p-SLC16A3 Prognosis, target treatment (56)

EMT, epithelial-mesenchymal transition; m6A, N6-methyladenosine; TMB, tumor mutational burden; TME, tumor microenvironment.

The role of SLC16A3 in HCC

Extensive studies have highlighted the pivotal role of SLC16A3 in the malignant progression of HCC. High expression of SLC16A3 has been consistently associated with tumor aggressiveness and poor prognosis. Multi-omics analyses and functional studies have demonstrated that SLC16A3 contributes to HCC development by regulating lactate metabolism, shaping the TME, modulating ferroptosis, and mediating chemoresistance, thereby emerging as a promising therapeutic target (57,58).

From a metabolic perspective, SLC16A3, a major lactate transporter, promotes lactate efflux and reinforces the Warburg effect. In HCC tissues and cell lines, SLC16A3 expression is markedly upregulated and positively correlated with tumor size, tumor-node-metastasis (TNM) stage, and vascular invasion (59,60). Knockdown of SLC16A3 significantly suppresses HCC cell proliferation, migration, and invasion (61), reduces extracellular lactate accumulation, and reverses the acidic microenvironment, ultimately attenuating glycolytic flux. Moreover, SLC16A3 expression positively correlates with hypoxia-inducible factor 1α (HIF-1α), further exacerbating hypoxia, angiogenesis, and tumor progression.

With respect to ferroptosis, SLC16A3 knockdown promotes the accumulation of reactive oxygen species (ROS), increases lipid peroxidation, and downregulates ferroptosis suppressors such as GPX4, DHODH, and SLC7A11, leading to ferroptotic cell death (Figure 2). Mechanistically, this process may involve reduced ERK phosphorylation and redox imbalance. In addition, SLC16A3 expression is positively associated with molecules in the Wnt/β-catenin signaling pathway (β-catenin, Cyclin D1, c-Myc), suggesting its regulatory role in cell survival-death balance via multiple signaling networks (62).

Figure 2 Mechanisms by which SLC16A3 modulates ferroptosis in cancer cells. ROS, reactive oxygen species.

SLC16A3 also plays a critical role in therapy resistance. High expression of SLC16A3 has been linked to resistance to chemotherapeutic drugs (e.g., gemcitabine) and targeted agents (e.g., lenvatinib). Silencing SLC16A3 sensitizes HCC cells to these agents (63), potentially through alleviation of hypoxia, reduction of lactate accumulation, and restoration of oxidative stress homeostasis. Furthermore, bioinformatic analyses have shown that elevated SLC16A3 expression is associated with increased tumor mutational burden (TMB) and higher expression levels of immune checkpoint molecules, including programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), suggesting that SLC16A3 may contribute to immune evasion in hepatocellular carcinoma (64,65).

Therapeutic strategies targeting SLC16A3 have attracted increasing attention in HCC. Preclinical studies have shown that siRNA-mediated silencing of SLC16A3 significantly suppresses HCC cell proliferation, migration, and invasion, while pharmacological inhibition of monocarboxylate transporters (MCTs) exhibits antitumor activity in vitro and in xenograft models. Notably, MCT inhibitors display distinct isoform selectivity; AZD3965 primarily targets MCT1 (SLC16A1), whereas Bindarit has been reported to inhibit MCT4 (SLC16A3)-associated lactate transport activity (66). These effects are largely attributed to disruption of lactate-dependent metabolic reprogramming and induction of ferroptosis. SLC16A3 inhibition may also alleviate the immunosuppressive TME by reducing lactate efflux and extracellular acidification, thereby enhancing antitumor immunity and potentially improving responses to anti-programmed cell death protein 1 (PD-1)/PD-L1 therapies. Given the limited efficacy of immune checkpoint inhibitor monotherapy in HCC, SLC16A3-targeted approaches may provide additional benefit and help overcome resistance to sorafenib and lenvatinib. A recent meta-analysis further demonstrated that elevated MCT4 expression is significantly associated with poor prognosis across multiple cancer types (67), supporting the clinical value of SLC16A3/MCT4 as both a prognostic biomarker and a therapeutic target.

SLC16A3 is central to the metabolic rewiring, microenvironmental remodeling, and therapeutic resistance of HCC. Simultaneously promoting glycolysis and immunosuppression, SLC16A3 emerges as a compelling therapeutic target. The development of potent and selective SLC16A3 inhibitors—either as monotherapy or, more likely, in combination with immunotherapy or existing targeted agents—holds great potential to improve outcomes in patients with HCC, marking an exciting direction for future clinical translation.

Conclusions

The survival rate of HCC remains alarmingly low, placing an immense physical and psychological burden on patients and their families. To effectively improve patient prognosis and quality of life, the identification and development of novel therapeutic strategies are urgently needed. Evidence indicates that SLC16A3 is associated explicitly with HCC and could serve as a valuable diagnostic biomarker. However, reliance on a single biomarker is insufficient to meet the practical demands of clinical management. Although a panel of multiple biomarkers can significantly enhance the early detection of HCC, this approach mainly strengthens the suspicion of the disease rather than providing definitive diagnostic or therapeutic guidance. Therefore, further in-depth investigations are warranted to improve the sensitivity and specificity of these biomarkers, ultimately enabling more precise and effective treatment strategies for patients.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-0772/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-0772/coif). The authors have no conflicts of interest to declare.

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Cite this article as: Li Z, Zhou Z, Liang S, Liu H, Sun Q, Li J. SLC16A3 links tumor metabolism to therapeutic opportunities in hepatocellular carcinoma. Transl Cancer Res 2026;15(7):566. doi: 10.21037/tcr-2026-0772

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