Vitamin C is a weak acid that is comprised of six carbon atoms and is classified as an α-ketolactone. In the human body, vitamin C mainly exists in two active forms, dehydroascorbic acid (DHA) and AA, in an interconvertible manner (Fig. 1A and B) (36). Vitamin C is abundant in a wide variety of fruits and vegetables and can only be obtained by humans via ingestion through dietary means, since humans cannot synthesize it. Following oral intake, vitamin C is primarily absorbed in the duodenum and upper jejunum, with minimal absorption occurring in the stomach. It enters the bloodstream through passive and active transport, facilitating its transmembrane movement (37,38). However, the majority of vitamin C is absorbed via the sodium-dependent vitamin C transporter (SVCT)1 (39,40). Vitamin C typically moves slowly across the plasma membrane, even in the presence of a notable concentration gradient. AA is absorbed in the intestine through SVCT1 (40), whilst DHA may undergo transmembrane diffusion and absorption through glucose transporters (GLUT) (41). However, the mechanism underlying AA absorption into the bloodstream is yet to be elucidated (42). Once AA is absorbed into the bloodstream, it is subsequently transported to various organs through SVCT2. Vitamin C is widely distributed across various organs and cells, with particularly high concentrations in the brain and endocrine glands, such as the pituitary and adrenal glands (37,43). A schematic diagram illustrating intestinal vitamin C absorption and distribution is presented in Fig. 1C and D. However, the majority of vitamin C entering the body is excreted by the kidneys, with only a small proportion eliminated through feces (41).

Via the SVCT2, vitamin C accumulates in key organs and cells, such as the skin, lymphocytes and neutrophils. The skin serves as the first line of defense for the body. Previous studies indicate that vitamin C reduces the synthesis and release of proinflammatory factors, such as IL-1β and TNF-α, by reducing the transcription of their genes (44,45). Additionally, vitamin C contributes to the tissue repair processes by promoting collagen synthesis and maturation, promoting the expression of angiogenic factors (such as VEGF), enhancing the expression of connective tissue regulators (such as connective tissue growth factor), increasing fibroblast activity, and activating important repair enzymes (such as heme oxygenase 1 and TGF-β) (44-46). In addition, preliminary evidence suggests that vitamin C can accumulate in neutrophils to an extent. Following infection, neutrophils can rapidly uptake DHA and convert it to AA within cells, leading to increases in its concentration. This concentration increase is calculated to be ~10 mM (36). In vitro and clinical studies also reveal that vitamin C can enhance the efficacy of phagocytosis and pathogen killing by promoting neutrophil chemotaxis (47,48). Lymphocytes, including T and B cells, are key types of immune cells that utilize SVCT2 for vitamin C storage. Although the precise mechanism by which vitamin C regulates lymphocyte physiology remains unclear (49), vitamin C can stimulate lymphocyte development, differentiation and maturation of immature cells, and regulate cytokine secretion (36,50,51). Additionally, when vitamin C is incubated with peripheral blood lymphocytes in vitro, it reduces the production of various inflammatory cytokines, such as TNF-α and IFN-γ, induced by lipopolysaccharide, whilst increasing the production of the anti-inflammatory cytokine IL-10 (50). Immunoregulatory T cells (Tregs), a subset of CD4⁺ T cells, serve an important role in immune regulation. They serve to prevent the hyperactivation of the immune system and maintain immune homeostasis. A recent study demonstrates that TET2 enzymes are important for maintaining a stable population of Treg cells (52). Vitamin C can enhance the activity of TET enzymes, suggesting that targeting TET enzymes with vitamin C may improve the efficacy of Treg cell induction (53).

Bcl2, the first gene found in the BCL2 family, inhibits apoptosis or programmed cell death (Table II). Bcl2 was named after it was found to be involved in follicular lymphoma, a cancer caused by a translocation between chromosomes 14 and 18, which increases the transcription of BCL2 (54). Previous studies demonstrate that the BCL2 family regulates cell death by inhibiting apoptosis and advancing the cell cycle, while also having antioxidant properties and participating in both pro-oxidant and antioxidant signaling pathways (55,56). The BCL2 family regulate the permeability of the mitochondrial membrane and induce the release of ROS to exert pro-oxidant effects (57). Additionally, the BCL2 family promotes the transcription of nuclear factor erythroid 2-related factor 2, which initiates an antioxidant response that reduces ROS levels, enhances cellular protection and growth, and contributes to tumor progression and drug resistance (58). Oxidative stress (OS) is caused by an imbalance between oxidants and antioxidants, which can lead to cellular damage or even destruction (59). It has an important function in regulating the fate of a cell, especially during the early stages of tumor development. This is because the production of ROS in the body promotes damage to cellular DNA, and along with a decrease in antioxidants, can lead to tumor development. By contrast, at later stages of malignant progression, tumor cells can produce a large number of antioxidants that either reduce or neutralize the production of ROS in the body in order to promote immune escape (60-62).

The Bcl2 gene is important in regulating programmed cell death or apoptosis. However, when the gene is mutated, the antiapoptotic and proapoptotic effects can become imbalanced, leading to various types of cancer, including lymphoma (63,64). DLBCL is particularly challenging in clinical management due to its heterogeneous nature. The BCL2 protein is overexpressed in ~10% of patients with DLBCL, which is associated with a reduced progression-free survival and a poor prognosis (65,66). In addition, the overexpression of BCL2 can reduce the production of oxygen-free radicals and lipid peroxides, creating a favorable environment for tumor cell proliferation (67-70). In oncogenic environments, pharmacological concentrations of vitamin C (0.3-20 mM) exerts a pro-oxidant effect by catalyzing the generation of hydrogen peroxide, which induces oxidative stress and selectively promotes the eradication of malignant cells, particularly in cases of liver, ovarian and breast cancer (71-73). A number of studies demonstrate that pharmacological doses of vitamin C (1-4 g/kg) can maintain the level of ROS in the body, preferentially killing various cancer cell lines whilst conferring minimal cytotoxicity to normal cells (29,32). In addition, vitamin C can increase the level of ROS, resulting in DNA damage and ATP depletion in tumor cells, promoting cancer cell apoptosis (27,74). Furthermore, vitamin C can inhibit the expression of BCL2, which activates the expression of the proapoptotic protein Bax, thereby further promoting the apoptosis of tumor cells (Fig. 2A) (27,75,76). Therefore, pharmacological doses of vitamin C may reduce the expression of BCL2 and increase the levels of ROS, leading to anticancer effects in DLBCL.

BCL6 is part of the antiapoptotic protein family and functions as a transcriptional repressor (77). The germinal center reaction pathway in mature B cells primarily uses BCL6, which serves an important role in promoting germinal center formation, regulating the cell cycle and participating in immune response signaling transduction. BCL6 inhibits the early activation and differentiation of germinal center B cells, rendering it an important regulatory factor for effective humoral immunity (77). In addition, BCL6 is indispensable for the development and function of T follicular helper cells and germinal center B cells (78,79). BCL6 was first identified in DLBCL. High expression of the BCL6 protein in germinal center B cells markedly inhibits the expression of the tumor suppressor p53. The inhibition of p53 enables lymphoma cells to survive in vivo and inhibits tumor cell apoptosis (78).

The oncogenic role of BCL6 is reported in lymphoma (80). As a transcriptional repressor, BCL6 inhibits the expression of cell differentiation markers (such as B-lymphocyte-induced maturation protein 1) (81), high-fidelity DNA repair genes (such as radiation sensitive protein 51) (82) and tumor suppressors (such as PTEN) (83). Concurrently, BCL6 promotes the expression of genes associated with the inhibition of apoptosis, cell cycle arrest, tumor cell proliferation and cell differentiation (84,85). In germinal center-derived BCLs, BCL6 functions as an oncogene, and is frequently associated with chromosomal translocations or promoter mutations that results in an aberrant overexpression (86,87). Mutations in the Bcl6 gene are frequently associated with a poorer prognosis and more aggressive disease course compared with cases with a non-mutated Bcl6 gene. Numerous studies indicate that 7-10% of patients with DLBCL exhibit gene rearrangements involving Myc Bcl2 and/or Bcl6, and that these are associated with an unfavorable prognosis (88,89).

As an important tumor suppressor gene, p53 regulates cell division, prevents DNA mutations and the proliferation of damaged cells, controls apoptosis, and inhibits tumor formation (90,91). Additionally, p53 halts the cell cycle and facilitates DNA repair (92). However, in DLBCL cells, vascular compression, due to rapid tumor cell proliferation, results in a hypoxic environment, which subsequently increases the expression of hypoxia-inducible factor-1 (HIF-1) in tumor cells. However, p53 competes with p300 proteins, which reduces the transcription of HIF-1α. Under sustained hypoxia, p53 induces the degradation of HIF-1α and triggers apoptosis, which are both important for inhibiting tumor growth (93-95). HIF-1 is expressed in most types of mammalian cell and primarily consists of the oxygen-dependent HIF-1α and the oxygen-independent HIF-1β. It can regulate the expression of genes that regulate metastasis, angiogenesis and tumor cell invasion. In DLBCL, BCL6 primarily inhibits p53, which in turn inhibits the effects of p53 on cell cycle arrest and apoptosis. Overexpression of BCL6 reveals reduced wild-type p53 expression levels, resulting in enhanced tumor cell proliferation and impaired apoptosis (79,96-98).

Vitamin C is a natural antioxidant. In normal cells, its antioxidant properties dominate because it directly reacts with superoxide anion radicals (O₂⁻) and hydroxyl radicals (OH⁻), which reduces the level of ROS within the cells (99). In tumor cells, vitamin C often acts as a pro-oxidant due to high metal ion concentrations in the cytoplasm of the cell (such as Fe²⁺), which leads to oxidative stress due to reactions such as the Fenton reaction. In addition, cancer cells also have an increased expression of GLUT1, which enhances the cellular uptake of oxidized vitamin C (DHA). This depletes the antioxidants such as glutathione, NADPH and superoxide dismutase, and increases the levels of ROS in the cytoplasm of the cell (32). Previous studies indicate that, at pharmacological concentrations, vitamin C can function as a pro-oxidant, selectively inducing DNA damage in cancer cells (71-73). This targeting facilitates the elimination of cancer cells. In cases of breast and cervical cancer, studies indicate that vitamin C upregulates the expression of wild-type p53 and inhibits HIF-1α activity, thus inhibiting tumor development (Fig. 2B and C) (74,100,101). Additionally, in DLBCL, pharmacological doses of vitamin C can increase wild type p53 production, indirectly modulating the impact of BCL6 overexpression. Furthermore, vitamin C can also inhibit HIF-1α activity, promoting apoptosis in tumor cells (102). In conclusion, vitamin C may be a potential anticancer therapeutic agent.

The Myc gene family, initially identified in Burkitt lymphoma, includes n-Myc, l-Myc and c-Myc (103,104). These genes promote cell proliferation, potentially leading to tumor formation. They exhibit distinct expression timelines and tissue specificity during development (105). c-Myc is broadly expressed across multiple types of tumors and during tissue development, and it is associated with tumorigenesis and prognosis (106). n-Myc is expressed in neural tissues and during the early phases of hematopoietic development, with important value in early tumor therapy (107). l-Myc is predominantly expressed in the lungs and is associated with tumor susceptibility and prognosis (106-108). Previous studies demonstrate the important role of Myc gene products, particularly c-Myc, in regulating cell death, proliferation, differentiation and malignant transformation (109,110).

c-Myc, a proto-oncogene, is located on chromosome 8q24. When overexpressed, c-Myc promotes cancer cells to re-enter the cell cycle and proliferate, which promotes tumor growth (111). Numerous studies demonstrate that the activation of Myc in cancer cells occurs through multiple mechanisms (112,113). For example, genetic mutations, chromosomal translocations and genomic amplifications can induce elevated Myc expression levels. Furthermore, alterations in an upstream regulatory pathway (such as Wnt/β-catenin) (114) can also increase Myc oncogene transcription levels. In addition, post-translational modifications of the Myc protein such as phosphorylation, proteasomal degradation and ubiquitination enhances its stability, resulting in the activation of the Myc pathway (115). As demonstrated in a conditional knockout mouse model, Myc is essential for hematopoietic system development (116). It regulates the balance between hematopoietic stem cell self-renewal and differentiation, and is also highly expressed in proliferating cells during lymph node development (117). In DLBCL, Myc is the third most frequently rearranged oncogene after BCL2 and BCL6. In total, ~15% of newly diagnosed patients with DLBCL have Myc gene rearrangements, and these patients are frequently associated with an increased level of tumor cell invasion and a poorer prognosis (118-120).

Previous studies demonstrate that vitamin C, acting as a pro-oxidant, increases the levels of ROS, which inhibits the growth of tumor cells (74,121,122). Previous studies using tumors such as clear cell renal carcinoma and esophageal cancer suggest that the accumulation of ROS inhibits the expression of c-Myc, induces DNA damage and reduces tumor cell proliferation (123,124). Another study reveals that the combination of vitamin C with a respiratory complex I inhibitor effectively eradicated c-Myc-overexpressing cells and enhanced treatment outcomes in human BCL xenografts (125). However, further research is required to elucidate the effects of vitamin C on human and hematological tumors. In summary, vitamin C has potential benefits in cancer treatment and may promote tumor cell apoptosis via the ROS/c-Myc axis.

The TME is a dynamic and intricate cellular landscape in which tumor or cancer stem cells coexist with immune cells (myeloid and lymphoid), fibroblasts, blood vessels, the extracellular matrix and a range of signaling molecules (such as C-X-C motif chemokine ligand 12 and IL-6) (126,127). A previous study indicates that the TME is adaptable, continuously altering its characteristics throughout tumor development and serving a role in regulating cancer progression (128). For example, immune cells within the TME transition between antitumor and protumor states in response to cytokines secreted by the TME. Cells that suppress the antitumor response include Tregs, myeloid-derived suppressor cells (MDSCs) and M2 phenotype tumor-associated macrophages (TAMs; Fig. 3) (129). Numerous studies indicate that the composition of immune cells in the TME, particularly endogenous immune cells (such as MDSCs, Tregs and M2 macrophages), is directly associated with unfavorable tumor treatment outcomes (130-132).

DCs are immune cells that originate from pluripotent hematopoietic stem cells in the bone marrow. These cells can be categorized into the classical DC (cDC) and lymphoid DC subtypes, with the latter known as plasma cell-like DCs (pDCs). cDC1 and cDC2, two subtypes of cDCs, are differentiated by the abundance of antigen-presenting molecules on their surfaces. These cells are highly specialized and proficient in stimulating naive antigen-specific CD4⁺ and CD8⁺ T cells through the processing and presentation of antigens, including tumor-associated antigens. This function is critical for the initiation of an adaptive immune response (133).

Previous studies indicate that DCs serve a role in the antitumor immune response (134,135). Specifically, cDC1 can recognize tumors, secrete factors that modulate the TME, present tumor-associated antigens, activate CD8⁺ T cell responses and enhance antitumor immune function (136-138). In addition, cDC2 can activate the CD4⁺ T cell response, thereby augmenting the ability of CD8⁺ T cells to kill tumor cells (139,140). IFN-I produced by pDCs serves an important role in the activation of stimulator of IFN response cGAMP interactor 1, which causes cell cycle arrest, regulates cell death and promotes the expression of proapoptotic proteins such as Bax and Bak. This increases the permeability of the mitochondrial membrane, which releases apoptotic factors such as cytochrome C, which in turn triggers the caspase cascade, leading to apoptosis (141). However, the TME in contrast can inhibit the differentiation and maturation of DCs (128), resulting in functional defects in their ability to stimulate T cells and drive antitumor immune responses, thereby promoting tumor growth (142-144). DC dysfunction occurs in various types of cancer, including colon cancer and melanoma (145,146), and is associated with a poor prognosis in patients with advanced-stage cancer (147,148). Consequently, activating DCs in the TME is advantageous for antitumor therapy, making it a promising target for immunotherapy.

DLBCL is a malignant lymphoma with a poor prognosis (18,149). Its TME is considered to serve a pivotal role in the development and prognosis of DLBCL. Various in vitro studies reveal that vitamin C can enhance the immunogenicity of DCs, improving their ability to secrete proinflammatory factors (such as IFN-γ and TNF-α) and promoting T cell differentiation (150,151). Furthermore, studies indicate that vitamin C can regulate the activity of the DNA demethylation enzyme TET2 and modulate the differentiation of DCs (152). Consequently, pharmacological doses of vitamin C can modulate DCs in the TME, enhance antitumor activity and mediate a synergistic effect with chemotherapy and immunotherapy (153).

TILs are CD4⁺ and CD8⁺ T cells that mature in the thymus and have immune functions in various organs and tissues throughout the body (154). CD8⁺ T cells initiate immune responses by killing cells through perforin and granzyme. They also produce a number of cytokines, such as TNF-α and IFN-γ, to enhance their activation (155). CD4⁺ T cells regulate immune responses by producing cytokines and inducing T cell differentiation (155). By contrast, Tregs serve to prevent excessive activation of the immune system and serve a crucial role in regulating tumor immunity (156).

Tumor growth is typically a slow gradual process, where the interaction between tumor cells and the immune system can reshape the immune environment, impacting T cell differentiation (157). In patients with cancer, a notable number of T lymphocytes migrate to the tumor site to attack the malignancy. However, prolonged exposure can lead to exhaustion, T cell depletion, cytokine production and the reduced ability to destroy tumor cells (157). Contributing to this, Tregs in the TME obstruct antitumor effects through various mechanisms, including the secretion of inhibitory cytokines (such as IL-10 and TGF-β) to reduce the antigen-presenting ability of DCs, inhibiting CD8⁺ T cells from targeting tumor cells and promoting immune evasion (158-160). This is observed in several types of solid tumors, including melanoma (161), hepatocellular carcinoma (162), lymphoma (163) and lung cancer (164).

Numerous studies reveal that the dysfunction of tumor-infiltrating T cells occurs gradually (165,166). Initially, a population of tumor-specific T cells is depleted during thymic maturation due to negative selection, limiting the antigen recognition ability of the remaining auto/tumor-specific T cells (167). Subsequently, in a non-inflammatory environment, the lack of innate stimulators (such as lipopolysaccharide) results in the weak activation of antigen-presenting cells, leading to the poor activation of tumor-specific T cells (167). Finally, the TME induces and maintains T cell hypo-responsiveness (168). PD-1 is a marker of T cell failure (164). Tumor-infiltrating CD8⁺ T cells express PD-1, which binds to PD-L1 on tumor cells, resulting in the inhibition of T cell activation and antitumor immunity. Treg cell-mediated immunosuppression is associated with the upregulation of PD-1 (169). Currently, PD-1 inhibitors are widely used in the treatment of various tumors (such as in lung and gastric cancer) and can effectively improve disease prognosis (170,171).

DLBCL is a prevalent type of non-Hodgkin's lymphoma. Study of the TME in DLBCL is becoming an increasingly popular research topic in the field of immunotherapeutics. Previous studies demonstrate immunological dysfunction in TILs and elevated PD-1 expression levels, both of which are associated with poor prognosis (172,173). Although PD-1 inhibitors (such as pembrolizumab and nivolumab) do not demonstrate objective remission rates in DLBCL, PD-1 inhibitors are considered safe, with good tolerance and promising prospects (174,175). Anti-PD-1 therapy is indicated to confer notable synergistic effects with vitamin C in a lymphoma mouse model (30,176,177). Vitamin C boosts antitumor immunity and improves anti-PD-1 therapy by increasing chemokine production and TIL (178). Vitamin C is known to enhance the activation of tumor-specific T cells by improving the antigen presentation ability of DCs (152). It also enhances T cell penetration into the tumor area to increase antitumor efficacy in combination with anti-PD-1 drugs (179). However, research on the role of Tregs in the antitumor effects of vitamin C remains warranted.

Macrophages serve a key role in both innate and adaptive immunity. They are primarily derived from bone marrow-derived monocytes and their phenotype and function depend on the surrounding microenvironment. There are two types of macrophages: Classical activation (M1 macrophages) and alternative activation (M2 macrophages) (180). In different tissue environments, macrophages can differentiate into specific subtypes. M1 macrophages function to reduce inflammation, as well as to phagocytose and kill target cells (181). By contrast, M2 macrophages are involved in angiogenesis, tissue repair, and tumor progression (182).

TAMs are the most common immune cells that infiltrate the TME. Their role in promoting tumor growth has been extensively studied (183). Recent studies have shown that macrophages in the TME are continuously transitioning between two states: M1 and M2 (184,185). During the early stages of tumor growth, macrophages primarily differentiate into tumor infiltrating M1 macrophages to promote the antitumor immune response. However, in the latter stages, they primarily differentiate into the M2 subtype to counteract the antitumor effect. In the TME, TAMs are predominantly of the M2 variety (178). They primarily promote angiogenesis, invasion, metastasis and tumor cell proliferation (180). TAMs exert their antitumor effects through three main mechanisms: i) Secretion of inhibitory cytokines, which inhibit CD8⁺ T lymphocytes from destroying tumor cells, such as TGF-β and IL-10 (181); ii) regulation of the epithelial-mesenchymal transition (EMT) and extracellular matrix remodeling, which contributes to the malignant biological characteristics and migration of tumor cells (182,183); and iii) tumor angiogenesis, in which growth factors (such as platelet-derived growth factor and VEGF) released by TAMs aid in tumor angiogenesis, creating blood vessels that promote tumor cell spread. These effects were indicated in several malignant types of tumor, including prostate, bladder and breast cancer (186). Therefore, TAMs serve a critical role in tumor development.

In DLBCL, TAMs are associated with disease progression. Their expression is inversely associated with DLBCL prognosis (187). A number of experimental studies reveal that vitamin C can induce the transformation of M2 macrophages into M1 macrophages to markedly enhance the oxidative toxicity of M1 macrophages, promoting the infiltration of tumor-killing T cells and enhancing antitumor effects (188-190). In summary, pharmacological doses of vitamin C, acting as a pro-oxidant, can promote the polarization of TAMs towards the M1 subtype in the TME. This promotes antitumor effects and facilitates TME remodeling.

MDSCs form a heterogeneous population of cells that suppress the immune system within the TME. They primarily inhibit the cytotoxic activity of T cells and natural killer cells, serving a role in tumor-mediated immune escape (127,191). MDSCs are primarily immature myeloid cells, consisting mainly of monocytes (M-MDSC) and polymorphonuclear cells (PMN-MDSC). Studies demonstrate that M-MDSC and PMN-MDSC are expanded in the majority of solid tumors, such as hepatocellular carcinoma (192) and melanoma (193). Although PMN-MDSC forms the predominant subgroup, a study by Azzaoui et al (194) demonstrates that M-MDSC is the most inhibitory subgroup, with the absence of PMN-MDSC not altering the tumor incidence. In colorectal and breast cancer, monocytes/M-MDSC can differentiate into TAMs within the TME and interact with TAMs to inhibit antitumor effects (195-197). This suggests that targeting MDSCs may enhance antitumor effects. It has been observed that a notable number of MDSCs can effectively impair T cell responses in DLBCL (194). Previous studies suggest that MDSCs serve a key role in early drug resistance following R-CHOP treatment for DLBCL (198,199). At present, to the best of our knowledge, the direct impact of vitamin C on MDSCs has not been studied. However, it is likely that vitamin C can mediate regulatory effects on DCs, TILs and TAMs within the TME to influence MDSCs by modulating the TME (200).