LDH is present in blood cells and lymphoid tissues. It is not only often used as a biochemical indicator for diagnosis and therapeutic monitoring of lymphoma, but for many years it has been considered to correlate with a poor prognosis in lymphoma patients. As an independent prognostic marker, it is one of the most important prognostic determinants of the international prognostic index (Project, 1993). LDH, consisting of the M and H protein subunits encoded by the LDHA and LDHB genes, respectively, is a tetrameric enzyme essential for lactate synthesis that reversibly catalyzes the conversion of pyruvate to lactate or lactate to pyruvate. It is assembled in a tissue-dependent manner in five different heterotetramers or homotetramers to form five isozymes: LDH-1 (4H), LDH-2 (3H1M), LDH-3 (2H2M), LDH-4 (1H3M), and LDH-5 (4M). The LDHA isoforms are predominantly expressed in skeletal muscle, and LDH-5 (LDHA4) prevents pyruvate from entering the mitochondrial tricarboxylic acid cycle (Markert et al., 1975) and promotes the conversion of pyruvate to lactate. Whereas LDHB isoforms are usually located in the heart and brain, LDH-1 (LDHB4) plays the opposite role, preferentially converting lactate to pyruvate (Ždralević et al., 2018; Feng et al., 2018). LDHA and its downstream signals, as potential biomarkers, are positively correlated with macrophage density, such as in glioblastoma. Recent studies have shown that LDHA activates two transcriptional co-activators, yes-related protein 1 (YAP1) and transcriptional activator 3 (STAT3), in glioblastoma cells through a directed extracellular signal-regulated kinase (ERK) pathway. They can coordinate the upregulation of C-C motif chemokine ligand 2 (CCL2) and CCL7, thereby triggering macrophage infiltration into the TME. Conversely, the recruited macrophages produce extracellular vesicles that release LDHA. LDHA inhibitors can not only regulate the inhibitory anti-tumor immune function of macrophages but also inhibit the growth and development of tumors (Khan et al., 2024).

Lactate production is inextricably linked to the regulation of LDH. Elevated serum lactate in patients with lymphoma is largely progressive (Ruan et al., 2021). Elevated LDH levels in patients with aggressive lymphoma may be due to increased cell renewal and hypermetabolism of the tumor. In malignant lymphomas, the intracellular mitochondrial machinery is altered, and apoptosis is dysregulated, and tumor cells release intracellular enzymes through damaged cell membranes (Jurisic et al., 2015). It suggests that abnormally enhanced tumor metabolism and tumor cell necrosis cause increased release of LDH into the blood. The rapid proliferation of tumor cells results in a hypoxic environment as well as mutations in certain oncogenes and oncostatin genes, such as HIF-1α and c-Myc, which enhance pyruvate production by accelerating the two rate-limiting steps in glycolysis involving hexokinase 2 (HK2) and fructose-2,6-bisphosphate. They also inhibit pyruvate dehydrogenase (PDH) phosphorylation by inducing pyruvate dehydrogenase kinase 1 (PDK1), which in turn inhibits its mediated mitochondrial metabolic activity of pyruvate. Meanwhile, both can induce LDHA gene expression and inhibit LDHB gene expression, further enhancing LDH-5 activity and decreasing LDH-1 activity (Feng et al., 2018). It ultimately leads to the conversion of pyruvate to lactate to promote the glycolytic process, resulting in increased lactate production and conversion of NADH to NAD+.

The characteristic glycolytic process described above leads to the accumulation of lactate in the cytoplasmic lysate (Warburg, 1924; Warburg and Research, 1925). Consequently, to prevent intracellular acidification, lactate and H exocytosis must be transported to the extracellular space and also exchanged between cell populations (Certo et al., 2021).

MCTs are plasma membrane transport proteins essential for lactate shuttling. MCTs are highly expressed in stromal cells of DLBCL. In addition to the high rate of glycolysis exhibited by lymphoma cells that produce excess lactate, a large amount of lactate produced by the cell must be transported out of lymphoma cells through MCTs (Gooptu et al., 2017), mediating the secretion and reuptake of lactate or pyruvate, thus preventing cell death caused by acidosis. This process resulted in an increase in lactate levels in TME. MCTs belong to a class of transporter proteins encoded by a family of solute carrier proteins, which consists of 14 members (Singh et al., 2023). The most common cytosolic-localized proton-coupled transporter proteins of monocarboxylates are c-Myc-mediated MCT1 and HIF-1α-mediated MCT4. MCTs facilitate the transport of lactate and pyruvate in cancerous cells (e.g., (Halestrap and Wilson, 2012; Halestrap, 2012)). They also facilitate lactate shuttling between cancer cells and stromal cells in the TME. MCT1 is the most widely expressed and has a relatively high affinity for lactate. It acts as a transporter according to local lactate concentration gradients. In contrast, MCT4 acts as an efflux transporter, primarily in highly glycolytic tissues. The transmembrane auxiliary protein CD147 ensures that MCTs function as transporter proteins in the correct orientation at the cell surface (Ippolito et al., 2019). Emerging evidence suggests that proton-coupled lactate efflux from tumor cells or stromal cells contributes to remodeling the TME to maintain an acidic phenotype and promotes tumor spreading, leading to angiogenesis and invasive metastasis as well as immune escape (Kirk et al., 2000), which is associated with poor prognosis (Parks and Pouysségur, 2017).

MCT1 and MCT4 are differentially overexpressed in solid tumors in a variety of cancer types, such as lung, colon, and renal cancers (Ruan et al., 2017; Nakayama et al., 2012; Kim et al., 2015). Evidence also exists in hematologic malignancies such as myeloma and lymphoma (Walters et al., 2013). The significant differential expression of MCT in different lymphomas has been demonstrated in multiple experiments. In NHL, adverse clinical pathological features are significantly correlated with the expression of MCT1 (Afonso et al., 2019). Studies have confirmed that in DLBCL and Burkitt lymphoma, MCT1 is expressed at high levels in the absence of significant expression of MCT4 (Noble et al., 2017). Another study showed that in ALK (−) anaplastic large cell lymphoma (ALCL) tumor cells as well as B cells, natural killer/T cells, T cells, and classical Hodgkin lymphoma, only MCT1 is widely expressed. The expression of MCT4 is mainly localized to adjacent stromal cells. By comparison, only ALK (+) ALCL cells have high expression of MCT1 on the tumor cell membrane and widespread expression of MCT4 (Choi et al., 2022). Similarly, in T-cell lymphoma tissue, both MCT1 and MCT4 are overexpressed and associated with decreased OS and PFS, indicating poor prognosis (Zhao et al., 2023). Therefore, therapeutic strategies that disrupt lactate transport may be promising approaches for treating lymphoma (Le Floch et al., 2011; Parks et al., 2013; Doherty and Cleveland, 2013). AZD3965 (a first-of-its-kind MCT1 inhibitor) has been used in phase I clinical trials for high MCT1/low MCT4 cancers targeting this target (Halford et al., 2023). Its therapeutic effect may be related to inhibiting lipid biosynthesis and increasing tumor immune cell infiltration involving dendritic and natural killer (NK) cells (Beloueche-Babari et al., 2020).

HIF-1 stimulates anaerobic glycolysis, which accumulates lactate and acidifies the TME, affecting cellular subpopulations in the TME including immune cells (Faubert et al., 2017). HIF-1α regulates the expression of genes encoding enzymes necessary for aerobic glycolysis (Darekar et al., 2012) and increases the production of metabolite lactate. For example, in myc-driven cell lines, HIF-1α and myc regulate the expression of HK2 and PDK1 (Mushtaq et al., 2015). The Warburg effect regulated by HIF-1α is observed in lymphoblastoid cells (Darekar et al., 2012; Mushtaq et al., 2015). During lactate metabolism, HIF-1α induces the overexpression of VEGF, which is involved in MCT protein 1-mediated lactate transport and subsequent inhibition of prolyl hydroxylase (PHD) (Horikawa et al., 2017; Rivera et al., 2015; Rivera and Bergers, 2015; Sonveaux et al., 2012). Inactivation of HIF PHDs will initiate transcription of target genes such as glucose transporter proteins, most glycolytic enzymes, MCT4, and VEGF (Semenza, 2003; Semenza, 2010). Finally, in solid tumors, HIF-1α-induced lactate promotes ferroptosis resistance in a pH-dependent manner, suggesting a promising therapeutic strategy (Yang et al., 2023). In the hypoxic microenvironment (HME) formed by malignant tumor cells, HIF-1α is more stable under the low pH condition of lactate formation and is not easy to be degraded, thus increasing its accumulation in cells (Zhao et al., 2024). HIF-1α regulates a variety of immune cells (such as T lymphocytes, macrophages, MDSCs) to modulate tumor immunity. In addition, it can also mediate the upregulation of PD-L1 and promote tumor immune escape (Noman et al., 2019; Deng et al., 2021). HIF-1α protein expression is also strongly dependent on some signaling pathways, such as PI3K/Akt/mTOR signaling pathway (Rashid et al., 2021).

HIF-1α is the best-studied isoform of the heterodimeric transcription factor HIF-1 and is normally expressed in human cells (Liu et al., 2020). Its overexpression is strongly associated with hematologic malignancies such as leukemia, lymphoma, and multiple myeloma (Zhao et al., 2024). Stabilization and upregulation of HIF-1α were observed in lymph node biopsies from both DLBCL and FL patients (Evens et al., 2008; Pangarsa et al., 2012). It can lead to overall translational repression as well as mitochondrial dysfunction during hypoxic stress in DLBCL and serves as one of the prognostic factors in assessing the likelihood of survival in DLBCL patients treated with R-CHOP (Evens et al., 2010). Furthermore, MYC and PI3K/AKT/mTOR independently increase HIF-1α expression (Pang et al., 2023). It has been demonstrated that HIF-1α may promote the viability and migration of activated B cell-like cells under hypoxia through the transcription of CXCR4 and activation of the AKT/mTOR pathway (Jin et al., 2023).

The immunosuppressive effect produced by HIF-1α is associated with the activation of several downstream effects. The HIF1α-VEGF signaling pathway described above regulates macrophage conversion to the M2 pro-angiogenic phenotype, thereby exerting a function in signaling (Colegio et al., 2014a; Kes et al., 2020). Moreover, lactate inhibits monocyte activation and dendritic cell differentiation by increasing HIF-1α stability (Colegio et al., 2014a; Gottfried et al., 2006; Nasi et al., 2013). As described above, lactate produced by activated DCs and other immune cells plays a role in regulating DCs by pathogenic autoimmune T cells through a HIF-1α-mediated mechanism (Sanmarco et al., 2023). This gives us new therapeutic ideas, but this mechanism remains to be further investigated and confirmed in hematologic malignant diseases.

The MYC oncogene plays a crucial role in a wide range of human solid tumors and various hematological malignancies, including B-cell and T-cell malignancies, especially infiltrative B-cell lymphomas such as DLBCLs and BLs (Pang et al., 2023; Aukema et al., 2011; Slack and Gascoyne, 2011), and it is considered to be a major regulator of cellular metabolism and proliferation (Dang, 2012). In lymphomas, MYC activation occurs through mutation, amplification, translocation, and various other molecular processes (Ott et al., 2013; Ruzinova et al., 2010; Leucci et al., 2008). MYC proteins, which are synergistic regulators of the Warburg effect with HIF-1α (Gordan et al., 2007), upregulate lactate production through multiple mechanisms. First, they enhance pyruvate production by accelerating two of the three rate-limiting steps of HK2 and pyruvate kinase (PK) as target genes for HK2 and fructose-2,6-bisphosphate in glycolysis. Second, they enhance the Warburg effect by inducing PDK1. They also phosphorylate and inactivate PDH, which reduces the conversion of pyruvate to acetyl coenzyme A, thereby allowing more pyruvate to be converted to lactate. Third, they activate LDH-5 and inhibit LDH-1, promoting the conversion of pyruvate to lactate (Feng et al., 2018; Dang et al., 2011; Clem et al., 2008).

Due to the increase of glycolysis rate, a large amount of lactate is produced, which then promotes the lactylation of histone to support the expression of c-myc (Pandkar et al., 2023). Myc regulates a series of innate and adaptive immune cells and guides their proliferation, maturation, activation and subsequent immune function events. For example, it coordinates T cell metabolic reprogramming and macrophage polarization (Wang et al., 2019; Gnanaprakasam et al., 2017; Gnanaprakasam and Wang, 2017). During immunization, the Treg-specific transcription factor, FOXP3, inhibits c-Myc signaling to reprogram Treg cell metabolism. It diverts Tregs to OXPHOS metabolism, thereby allowing Treg cells to remain active and become more adaptive in low glucose and high lactate TME (Angelin et al., 2017). In addition, Myc induces and regulates the expression of immune checkpoints, including PD-L1 (Casey et al., 2017). In turn, myc itself is regulated by other signaling pathways, such as the NF-κb pathway in B cells. If it is damaged, the myc protein of B cells cannot be upregulated after mitotic stimulation, leading to the growth defect of mature B cells (Grumont et al., 2002; Grumont et al., 2004).

In the context of normal development, the malignant transformation of mature B cells in the germinal center or more differentiated B cells in the secondary lymphoid organs gives rise to B cell lymphoma (Scott and Gascoyne, 2014). The attack of immature B cells by exogenous antigens occurs mainly in the germinal center, a process that is tightly regulated by highly coordinated interactions between immune cells and stromal cells. The microenvironmental components of malignant B cells include a stromal component (stromal cells, vasculature, and extracellular matrix) and an immune cell component (T cells, macrophages, dendritic cells (DCs), and NK cells) (Scott and Gascoyne, 2014; Nicholas et al., 2016; Basso and Dalla-Favera, 2015). The presence of these immune cells was recently validated in a B-cell lymphoma study cohort. First, the study identified CD4 or CD8 T cell subclusters. The infiltrating T cells were classified as naïve T cells, cytotoxic T cells, regulatory T cells (Tregs), or helper T cells. The helper T cells were subsequently identified as follicular T cells (Tfh) or helper T cells 17 (Th17). In addition, six myeloid cell subclusters could be identified, including three macrophage subclusters (MPs) (CD68, CD14, and CSF1R), two conventional DC subclusters (cDCs) (CLEC9A and LAMP3), and one plasma cell-like DC subcluster (pDC) (CLEC4C) (Steen et al., 2021) (Figure 2). They affect tumor growth and behavior through their interaction with tumor cells, thereby affecting the survival rate of patients. The microenvironment of T-cell lymphoma includes multiple cell types, extracellular matrix, and soluble factors (Giudice, 1967).

In the development and progression of lymphoma, the innate and adaptive immune systems work in concert. The most important effector cells are NK cells and T cells (Taylor and Gribben, 2015). Available evidence suggests that due to the heterogeneity of the immunological profile of TME, the composition of T-cell and NK-cell specific genes that characterize T-cell phenotype can effectively predict the prognosis of DLBCL patients (Autio et al., 2021).

Tumor-infiltrating macrophages (also known as tumor-associated macrophages, TAM) are usually the most abundant immune cells in the TME in hematologic malignancies, including lymphomas (Franklin et al., 2014; Cassetta and Pollard, 2018). Macrophages are classified as M1/classically activated and M2/alternately activated. Based on the M1 and M2 phenotypes of TAM, M1 macrophages were found to have tumor cell killing and anti-angiogenic effects. However, M2 macrophages are preferentially located in the hypoxic zone of the tumor, which has a strong inflammatory profile (Serna et al., 2023; Cai et al., 2012), and they perform immunosuppression and promotes angiogenesis and metastasis through the expression of HIF-1α, which induces the transcription of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), etc (Brigati et al., 2002; Marinaccio et al., 2014). In tumors, TAM is mainly composed of the M2 subtype (Mantovani et al., 2017). Various studies have demonstrated that the pro-angiogenic M2 TAM found in DLBCL (Shen et al., 2016), with increased numbers, is an independent predictor of shorter overall survival (OS) and progression-free survival (PFS) in lymphoma patients and is strongly associated with poor prognosis (Wada et al., 2012; Nam et al., 2014; Marchesi et al., 2015; Steidl et al., 2010). This depends specifically on the macrophage phenotype, either M1 (CD68/HLA-DR) or M2 (CD68/CD163) (Riihijärvi et al., 2015). Their results showed that higher CD68 expression of TAM in DLBCL patients was associated with worse outcomes (Cai et al., 2012). In conclusion, TAM plays an active role in enhancing angiogenesis in human lymphoma. It not only promotes the generation, repair, and remodeling of blood vessels and lymphatic vessels, and the growth and proliferation of lymphoma tumor cells, but also inhibits adaptive immunity, worsens patient prognosis, and enhances drug resistance (Xiong et al., 2022; Ribatti et al., 2024).

A critical factor in maintaining the tumor-promoting activity of TAM is elevated lactate levels. The mechanism by which lactate induces TAM-promoting tumor expansion is primarily through the production of VEGF and the promotion of TAM polarization to an M2-like phenotypic tumor-promoting state (Stockmann et al., 2008). In M1 TAM, lactate inhibits its function by decreasing the expression of IL-6, iNOS, and CCL2 (Certo et al., 2021). For M2 TAM, the expression of 2 transcription factors (HIF-1α and HIF-2α) is key (Pugh and Ratcliffe, 2003; Murdoch et al., 2008). Lactate signaling induces HIF-1α-dependent polarization of macrophages and activates the lactate/HIF-1α/VEGF signaling axis, which upregulates the expression of the arginine metabolizing enzyme arginase 1 (Arg 1) to provide a substrate for cancer cell proliferation to support tumor growth and upregulates VEGF to induce neovascularization to achieve a tumor-promoting state (Chang et al., 2001; Qian and Pollard, 2010). In addition, this signaling axis also induces a variety of other genes, including Fizz1, Mgl1, and Mgl2 (Colegio et al., 2014b). Second, macrophages express G protein-coupled receptor 132 (GPR132) at high levels on their surface. When macrophages sense extracellular lactate, it induces the expression of cyclic adenosine monophosphate (cAMP) and the early inhibitory protein (ICER), which upregulates ARG1, VEGF, and HIF-1α, and can also lead to M2 macrophage polarization (Chen et al., 2017). Finally, lactate actively downregulates Atp6v0d2 expression in TAM through mTOR-dependent inhibition of TFEB, a transcriptional regulator of lysosomal proteins. This inhibition mediates lysosomal degradation of HIF-2α in macrophages, and maintenance of HIF-2α leads to enhanced tumor vascularization and growth (Liu et al., 2019).

Another recent study found that lactate can also be HIF1α-independent under prolonged hypoxic conditions. NDRG3 is spared from degradation in a PHD2/VHL-dependent manner by binding to lactate, similar to HIF1α under normoxic conditions. This leads to increased NDRG3 and activation of the RAF-ERK pathway (Certo et al., 2021). Moreover, the B-cell junction of PI3K (BCAP) exacerbates the above process by promoting the reparative transformation of macrophages through histone lactonylation. It controls the pathophysiological responses associated with hypoxia, including inflammation and angiogenesis in turn (Irizarry-Caro et al., 2020; Chen et al., 2021).

Lactate-derived histone lysine lactylation (Kla) has a regulatory role in gene expression in macrophages. Kla levels are elevated when increasing concentrations of lactate treat the model system of bacterial-exposed M1 macrophages. That is, in the aerobic glycolysis that occurs during polarization of M1-type macrophages, lactate initiates a “lactate clock” by mediating the modification of the lysine at position 18 of histone H3 (Zhang et al., 2019; Latham et al., 2012). This modification drives the expression of M2-like genes during the late phase of M1-type macrophage polarization. ARG1 expression is also supported at these later stages. In addition, histone acetylation levels in the TME are associated with the production of M2 macrophage-related cancer genes (Zhang et al., 2019).

DCs are activated after phagocytosis and processing of antigens and are potent stimulators of the immune response against foreign antigens (Austyn, 1998). They upregulate MHC, co-stimulatory molecules, and adhesion molecules during effective antigen presentation and can stimulate naïve T cells. However, the role of DCs in lymphomagenesis is not clear, though their presence is indispensable. DCs influence tumor growth through interactions with tumor cells and T lymphocytes. Recent evidence suggests that in malignant hematologic diseases, DC loads tumor-specific antigens and generates specific anti-tumor T-cell responses (Davison, 2010). One study found that in NHL, the expression of CD62L and CCR7 (receptors essential for homing lymph nodes) was significantly reduced, leading to phenotypic alterations reduced numbers of DCs, and loss of tumor control (Fiore et al., 2006).

However, several studies have found that DCs also promotes local T-cell tolerance and an inflammatory environment. Higher ECOG scores and poorer outcomes in lymphoma patients have been associated with CD14⁺ DCs in tumor tissue (Gršković et al., 2022). Furthermore, in the Eμ-Myc model, the C/EBPβ transcription factor controls the expression of lymphoma-associated cytokines and leads to the suppression of T-cell responses to lymphoma by DCs (Rehm et al., 2014). Another study found that mice lacking the co-stimulatory receptor CD137, which is involved in the crosstalk between DCs and germinal center B cells, have a strong susceptibility to germinal center B-cell lymphomas (Middendorp et al., 2009). Finally, in T-cell lymphocyte proliferation, monocyte-derived cells fail to mature into DCs and protect tumor cells by preventing their death due to tumor IL-10 secretion (Wilcox et al., 2009). These findings demonstrate that the absence of DCs delays the progression of lymphoma.

High concentrations of lactate in the TME have been shown to contribute to the maturation and differentiation of DCs, enhance co-stimulatory molecule expression, and improve the uptake, processing, and presentation of antigens (Vermeulen et al., 2004; Tong et al., 2011). In contrast to this positive effect, most studies prefer an inhibitory effect.

First, lactic acidosis can both delay monocyte differentiation into DCs (Certo et al., 2021), impeding DC maturation, and induce monocyte differentiation into DCs with an immunosuppressive phenotype during antigen-specific autologous T cell stimulation (Nasi et al., 2013; Sutherland, 1988; Erra Díaz et al., 2020). In both allogeneic and autologous experimental settings, it was observed that lactate altered the antigen expression of DCs (immature/mature DCs, Langerhans cells) and strongly inhibited antigen presentation. In addition, a significant reduction in interleukin 12 (IL-12) secretion by DCs was found in both TADCs in MCTS co-cultures and controls supplemented with lactate during activation (Gottfried et al., 2006). In mouse gliomas, the glycolysis inhibitor diclofenac treated the inability of DCs to produce IL-12 in response to Toll-like receptor stimulation in vitro (Chirasani et al., 2013).

Secondly, Brown et al. reported that lactate activates G protein-coupled receptor 81 (GPR81, also known as hydroxycarboxylic acid receptor 1 or HCAR1) in DCs, which inhibits cell-surface presentation of MHCII, exerts a paracrine effect and prevents the presentation of tumor-specific antigens to other immune cells (Brown and Ganapathy, 2020). Raychaudhuri et al. found that lactate mediates the production of IL-12 through the intracellular GPR81 receptor on the surface of plasma cell-like dendritic cells (pDC). Or, the activation of calmodulin phosphatase signaling is triggered directly by cytoplasmic input from pDC via cell surface MCT proteins. Ultimately, it leads to an increase in free cytoplasmic calcium ions. It can inhibit pDC activation and type I IFN production, and affect the cellular metabolism required for effective pDC activation, leading to a tolerant phenotype (Vignali et al., 2008).

Finally, lactate contributes to the induction of Foxp3+ CD4⁺ Tregs, the major immunosuppressive cell subset in the TME, by enhancing the metabolism of tryptophan and the production of kynurenine in pDC (Raychaudhuri et al., 2019). In conclusion, in DC, excessive lactate levels in the TME impair induced monocyte differentiation and inhibit DC activation, cytokine production, and initiation of T cells.

Myeloid-derived suppressor cells (MDSC) are a diverse group of immature myeloid cells. In addition to Tregs, MDSCs are another cell population that promotes an immunosuppressive microenvironment (De Veirman et al., 2014; Rodriguez et al., 2010; Almand et al., 2000) and plays a role in tumor induction and progression as well as immune evasion. In different lymphoma subtypes, an increase in the number of MDSCs leads to cancer progression and is associated with poor clinical outcomes (Betsch et al., 2018). This immunosuppressive effect was found to be associated with MDSC secretion of T-promoting cytokines and chemokines in mouse lymphoma studies (Schlecker et al., 2012). In addition, MDSC may play an important role in tumor tolerance as T-specific tolerogenic antigen-presenting cells (APCs) (Serafini et al., 2008).

Lactate in TME in the form of histone H3K18 lactylation modification promotes the expression of RNA methyltransferase METTL3 in tumor-infiltrating myeloid cells (TIMs). In addition, the zinc finger structural domain of METTL3 is lactonated. These effects promote mRNA methylation of Jak1 and enhance activation of the JAK1-STAT3 signaling pathway by interacting with YTHDF1 to increase translation efficiency. It promotes the immunosuppressive function of TIMs and mediates tumor immune escape (Xiong et al., 2022).

In NHL, MDSCs are regulated by NK cells. MDSCs express NKG2D ligands and activates NK cells to produce large amounts of IFN-γ (Sato et al., 2015; Nausch et al., 2008). This cell subset is inversely proportional to the number of NK cells and increases with NK cell depletion. Lactate inhibits NK cell function and increases MDSC, which can contribute even further to the inhibitory microenvironment (Husain et al., 2013).

PD-1 is a surface inhibitory receptor expressed by macrophages, DCs, and T cells (Freeman et al., 2000). PD-1 binds to PD-L1 (expressed on the surface of APCs) and inhibits T-cell cytokine production and cell-cycle progression (Keir et al., 2008). The prevalence of PD-1 expression in DLBCL ranges from 39.5% to 68.6% and is usually increased on tumor-infiltrating T cells (Yamamoto et al., 2008), with higher levels being associated with poorer prognosis (Zhang et al., 2015; Zhang et al., 2016). PD-1 blockade has shown promise in phase 1 trials in DLBCL (Xu-Monette et al., 2018). Furthermore, numerous experiments have shown that PD-L1 is similarly highly expressed in lymphoma cells (Li et al., 2018). The DLBCL subgroup with PD-L1 is associated with a poor prognosis compared to the PD-1-negative subgroup (Laurent et al., 2015; Kiyasu et al., 2015).

It has been shown that M2-like macrophages, Treg cells, and certain inhibitory molecules (e.g., PD-L1) can be involved in mediating HIF1α-VEGF signaling pathway activity, leading to more active lactate metabolism (De Saedeleer et al., 2012; Seth et al., 2017; Vaupel and Multhoff, 2016). Conversely, lactate can also impact PD-1 expression. Lactate regulates the active checkpoint of Treg cell function in TME by upregulating PD-1 expression. As shown previously, Treg cells acquire higher PD-1 expression than effector T cells in highly glycolytic tumors. This mechanism means that lactate can upregulate PD-1 expression to enhance Treg cell function in TME and inhibit effector T cell activity, which promotes immune escape from lymphoma (Kumagai et al., 2022). Similarly, Feng et al. reported that tumor cell-derived lactate mediates the upregulation of PD-L1 through activation of its receptor GPR81, which is dependent on LDHA, and this in turn regulates macrophage polarization and allows tumor cells to evade cytotoxic T-cell targeting (Feng et al., 2017).

CTLA-4 is an inhibitory surface receptor with significantly elevated expression in lymphoma tissues and is an indicator for the early diagnosis and clinical treatment of lymphoma. It increases the proportion of lymphoma stem cells and induces the proliferation of Treg cells through the TGF-β pathway, which promotes the growth of lymphoma and recruits more immunosuppressive cells. CTLA-4 inhibits anti-tumor immune response and is closely related to the malignancy of lymphoma (Chen et al., 2021). Lactate promotes CTLA-4 expression in a Foxp3-dependent manner and promotes ubiquitin-specific peptidase 39 (USP39)-mediated RNA splicing in tumor-infiltrating Treg cells. This lactate-Foxp3-USP39-CTLA-4 signaling axis mediates high expression in tumor-infiltrating Treg cells in order to maintain Treg cell immunosuppressive function (Ding et al., 2024).

VISTA is a macrophage-negative immune checkpoint regulator that is highly expressed in tumor-infiltrating myeloid cells. In T-cell lymphomas, VISTA expression (88.1%) was found predominantly in CD68⁺ macrophages, and it was much higher than the expression of PD-L1 (68.7%) (He et al., 2021; Murga-Zamalloa et al., 2020). In a study of B-cell lymphoma, VISTA was found on the surface of monocytes from all patients. Its activation drove macrophages towards an M2-like pro-tumorigenic phenotype and promoted cancer cell phagocytosis. It also reduces the antigen-presenting ability of T cells at acidic pH (Lin et al., 2024), and mediates the binding of multiple histidine residues along the edge of the extracellular structural domain of VISTA to the adhesion and co-inhibitory receptor P-selectin glycoprotein ligand-1 (PSGL-1), which selectively participates in the inhibition of T cell proliferation and cytokine production. The development of acidic pH-selective antibodies against VISTA or its receptor PSGL-1 has been shown to reverse immunosuppression in vivo (Johnston et al., 2019). Considering that lactate can influence the pH of TME (Volk et al., 1993), it may affect the immune content associated with VISTA.

Activation of the PI3K/AKT/mTOR pathway occurs in lymphoma and is associated with p53, HIF-1α, and MYC (Sander et al., 2012; Argyriou et al., 2011; Wong et al., 2010; Rasul et al., 2012). A study found that mice expressing active Akt in lymphocytes progressively develop autoimmunity and lymphoma (Rathmell et al., 2003). mTOR is a ubiquitously expressed and highly conserved serine/threonine kinase downstream of PI3K/AKT. Transcription of several metabolic genes requires the involvement of mTOR complexes 1 and 2 (mTORC1 and 2) activation (Inoki et al., 2005). Sustained activation of mTORC1 occurs in a large number of hematopoietic and non-hematopoietic malignancies (Sabatini, 2006). It controls of a range of metabolic processes including glycolysis and mitochondrial metabolism (Laplante and Sabatini, 2013; Guertin and Sabatini, 2007). Therefore, aberrant activation of the PI3K/AKT/mTOR signaling pathway leads to enhanced metabolic activity in NHL (Blachly and Baiocchi, 2014). Lactate concentration can reflect the activation of mTOR signaling pathway in B-cell lymphoma (Lee et al., 2013). Increased lactate can result in reduced glucose consumption, upregulation of mitochondrial respiratory genes, and inhibition of mTORC1 activity (Erra Díaz et al., 2020). It promotes the differentiation of monocyte-derived DCs.

Following lactate efflux, mTORC1 is inhibited, which inhibits the production of pro-inflammatory cytokines and the cytotoxic activity of T cells (Balgi et al., 2011). Extracellular acidosis inhibits the mTOR signaling pathway and downregulates protein synthesis (Balgi et al., 2011; Pouysségur et al., 1982) thereby impairing immune cell function. For example, impaired NKT cell function leads to a reduction in effector factors (Xie and Bai, 2016), interfering with the antitumor effects of natural NK.

Changes in lactate metabolism can be associated with dysregulation of NF-κB signaling (Kooshki et al., 2022). Lactate flows into endothelial cells through MCT1 to induce the activation of NF-κB and support the drive of tumor angiogenesis (Scott and Gascoyne, 2014). The majority of B-cell lymphomas are known to activate constitutive phenotypes of the NF-κB pathway, which in turn promotes sustained lymphocyte proliferation and survival. Recent studies have confirmed that NF-κB is expressed in DLBCL and correlates with poor prognosis. It is considered to be an important pathogenic factor and one of the major therapeutic targets in lymphoma (Scott and Gascoyne, 2014; Zhang et al., 2016; Jost and Ruland, 2007; Davis et al., 2001; Yu et al., 2017; Ben-Neriah and Karin, 2011).

NF-κB signaling pathway is involved in the regulation of lactate on immune cells. Lactate can regulate macrophage phenotype through its receptor GPR81-mediated AMPK/LATS activation, which inhibits lipopolysaccharide (LPS)-stimulated NF-κB (Yang et al., 2020). Furthermore, Puig-Kroger et al. demonstrated that lactate impairs the maturation of MDDC phenotype and function induced by LPS, which is mediated by the inhibition of NF-κB activation. Furthermore, the pathway has been demonstrated to reduce the production of inflammatory cytokines (CCL2 and TNFα) in monocytes (Jost and Ruland, 2007; Peter et al., 2015; Dietl et al., 2010).