Changes in immune responses and the immune escape of H. pylori are closely associated with tumor-associated macrophages (TAMs), which are emerging key players in the TME. Macrophages play crucial roles in host defense against bacterial infections and in the regulation of immune responses during H. pylori infection (68). However, macrophages can also induce angiogenesis and suppress the host immune response during cancer development (37, 69). Generally, TAMs comprise M1 and M2 subtypes (27). Proinflammatory activated M1 macrophages promote the type I T helper (Th1) immune response by producing type I proinflammatory cytokines such as IL-1β, IL-1α, and IL-6 to clear pathogens and inhibit tumor progression, while simultaneously suppressing Th2-type responses (27, 70, 71). Activated M2 macrophages contribute to production of ECM and anti-inflammatory effectors such as IL-4 and IL-10 that are involved in the Th2 immune response, promotion of wound healing, and suppression of Th1 responses (72–75). Additionally, a third type called regulatory macrophages (Mregs) secrete abundant IL-10 that limits inflammation but do not secrete ECM (72). Helicobacter pylori and other pathogens might impair M1 macrophage differentiation while inducing M2 macrophage differentiation or M1 transdifferentiation into M2 macrophages, which can promote tumor progression and invasion by inducing angiogenesis and mediating immunosuppressive signals in solid tumors (27).

Furthermore, H. pylori infection might regulate specific microRNAs (miRNAs) to control macrophage function and affect the TME (28, 76). Infection with H. pylori leads to the downregulated expression of miR-4270 by human monocyte-derived macrophages. This favors upregulation of expression of CD300E immune receptors that enhance the proinflammatory potential of macrophages. However, the expression and exposure of major histocompatibility complex class II (MHC-II) molecules on the plasma membrane are simultaneously compromised. Hence, antigen presentation ability is decreased, leading to persistent H. pylori infection (28). The upregulation of let-7i-5p, miR-146b-5p and miR-185-5p, and miR146b expression in macrophages caused by H. pylori infection can similarly decrease HLA-II expression on the plasma membrane, which ultimately compromises bacterial antigen presentation to Th lymphocytes and impairs immune responses against H. pylori (29, 30). Collectively, H. pylori infection mainly downregulates surface recognition factors at the transcriptional level by rendering macrophages fail to degrade the bacteria. Thus, macrophages become a protective niche for H. pylori.

Helicobacter pylori can induce the production of specific enzymes that regulate macrophage function and affect TME. The production of arginase II (Arg2) in macrophages induced by H. pylori infection results in cell apoptosis and restrained proinflammatory cytokine responses, thus promotes H. pylori immune evasion (31, 32). Matrix metalloproteinase 7 (MMP7) plays a pivotal role in H. pylori-mediated immune escape (33). Heme oxygenase-1 (HO-1) expression in macrophages also be induced, resulting in a polarization switch towards a reduction in the M1 population and an increase in the Mreg profile, causing innate and adaptive immune responses failure (34). Transfer exosomes expressing mesenchymal–epithelial transition (MET) factor, a cell-surface receptor tyrosine kinase from H. pylori‐infected GC cells, can elicit uncontrolled macrophage activation and downstream inflammation and might be associated with tumorigenesis and cancer development (35). These findings shed light on how H. pylori influences the gastric microenvironment by inducing the expression of macrophage-associated enzymes in TAMs.

Moreover, H. pylori upregulates the expression of Jagged 1, a ligand of Notch signaling that plays an important role in M1 macrophage activation and bactericidal activity to prevent H. pylori infection. Upregulated Jagged 1 expression induces an increase in the expression of proinflammatory mediators and phagocytosis and a decrease in the bacterial load, which together impart antibacterial activity in macrophages (36). The hedgehog (HH) signaling pathway also plays an important role in the gastric TME. Sonic hedgehog (SHH) induced by H. pylori infection acts as a macrophage chemoattractant, which is a prerequisite in the gastric immune response (37).

In conclusion, H. pylori infection at the early stage can induce the infiltration of polymorphonuclear leukocytes and mononuclear phagocytes in the gastric mucosa as an innate immune response (77). During the advanced stages of GC, H. pylori can escape immune surveillance by impairing the antigen presentation of TAMs or by disrupting the M1/M2 (or Mreg) balance in favor of an M2 (or Mreg) phenotype (34, 72). Immunosuppressive status eventually promotes tumorigenesis and cancer development (78). These mechanisms also provide the potential for investigating novel targeted drugs (79). Specific miRNAs such as let-7i-5p, miR-146b-5p, and miR-185-5p can be targeted to reduce adverse effects on macrophage antigen presentation (29). Targeting specific enzymes including MMP7 and HO-1 or signaling pathways, such as Notch and HH, to regulate the M1/M2 (or Mreg) balance might also warrant investigation (33, 34).

Multipotent mesenchymal stem cells (MSCs) can self-renew and differentiate into various cell types that play key roles in tissue healing, regeneration, and immune regulation (80). Bone marrow-derived mesenchymal stem cells (BM-MSCs) might play important roles in H. pylori-associated gastric tumorigenesis and immunosuppression. Upon sensing signals indicating gastric mucosa damage, BM-MSCs migrate from bone marrow to stomach via the peripheral circulation. BM-MSCs heal damaged mucosa through a paracrine mechanism and directed differentiation (81, 82). H. pylori-induced persistent inflammation is required for BM-MSC migration and tumorigenesis (43, 83). Upregulated C-X-C chemokine receptor type 4 (CXCR4) interacts with its ligand, stromal-derived factor (SDF-1) and then promote BM-MSC migration to the gastric tissues (38).

Gastric epithelial glands become repopulated with BM-MSCs in mice model one year after H. pylori infection (39). After recruitment to stomach, BM-MSCs can become entrapped in a microenvironment containing H. pylori and malignant cells, 25% of which originate from BM-MSCs. Fusion with epithelial cells might render BM-MSCs more susceptible to malignant transformation or lead to the promotion of cancerous processes (40). BM-MSCs gradually acquire a clonal advantage and undergo stepwise transformation to malignant cells (39). During malignant progression, gastric epithelial glandular units undergo monoclonal transformation, resulting in emerging cancer stem cell (CSC) clones and adenocarcinomas (39, 41). Human adipose-derived mesenchymal stem cells (hA-MSCs) also participate in gastric tumorigenesis by increasing tumor cells invasion and metastasis during H. pylori infection (42).

In addition to malignant transformation, MSCs can promote tumorigenesis locally and systemically by compromising cancer immune surveillance or altering tumor stroma. When transplanting BM-MSCs in H. pylori infected mice model, IL-10 and transforming growth factor-β1 (TGF-β1) can be increased, as well as T cells secreting IL-10 and CD4⁺ CD25⁺ Foxp3⁺ regulatory T (Treg) cells in splenic mononuclear cells (43, 44). BM-MSCs can reduce the fraction of T cells that produce IFN-γ, thus inhibiting CD4⁺ and CD8⁺ T cell proliferation. Local and systemic immunosuppression mediated by BM-MSCs contributes to GC development induced by H. pylori (43).

MSCs can also promote tumorigenesis by altering tumor stromal components. Thrombospondin (THBS) promotes tumorigenesis through crosstalk with BM-MSCs. Infection with H. pylori significantly upregulates the expression of THBS4 in BM-MSCs. Overexpressed THBS4 then mediates BM-MSC-induced angiogenesis in GC by activating the THBS4/integrin α2/PI3K/AKT pathway (45). Moreover, BM-MSCs can differentiate into pan-cytokeratin-positive (pan-CK⁺) epithelial cells and alpha-smooth muscle actin (α-SMA⁺) cancer-associated fibroblasts (CAFs) by secreting THBS2, thus promoting the development of H. pylori-associated GC (46).

BM-MSCs play pivotal roles in H. pylori-associated GC. The immune regulatory functions of MSCs remain obscure. Shedding light on these functions and their mechanisms will provide clues on therapeutic targets for preventing GC development.

CAFs are activated myofibroblasts that accompany solid tumors and are principal constituents of tumor stroma (84, 85). They play important roles in the TME. They can create a niche for cancer cells and promote cancer progression by stimulating cancer cell proliferation, migration, invasion, and angiogenesis (85–87). Proinflammatory and tumor-associated factors secreted by CAFs might induce persistent inflammation or intervene in tumor immunity, thus mediate tumor immune escape (52, 88). Mainly derived from MSCs, CAFs could induce epithelial-mesenchymal transition (EMT), which enhances the invasive properties of malignant cells (89, 90) that detach from primary tumor site to surrounding tissues (91).

Helicobacter pylori infection can induce MSCs differentiating into CAFs, and upregulate the expression of fibroblast markers, fibroblast activation protein (FAP), CAF activation markers, and aggressive/invasive markers (47). FAP-positive CAFs enhance the survival, proliferation, and migration of GC cell lines and inhibit T cells function (48). H. pylori infection also increases the expression of hepatoma-derived growth factor (HDGF) (49, 50). Exposure to HDGF promotes the recruitment of BM-MSCs, stimulates their differentiation into CAF-myofibroblasts, and enhances tumor cell proliferation, invasiveness, and metastasis (49). Moreover, H. pylori infection can induce fibroblasts transdifferentiating into myofibroblasts, which upregulating the early carcinogenic marker hypoxia-inducible factor 1-alpha (HIF-1α) and downregulating proapoptotic bcl-2-like protein 4 (Bax) expression (51).

CAFs induced by H. pylori propel EMT by nuclear factor kappa B (NF-κB), signal transducer and activator of transcription 3 (STAT3), and TGF-β. Helicobacter pylori might induce the activation or differentiation of rat gastric fibroblasts in vitro, which then activate NF-κB and STAT3 signaling, and upregulate Snail1. This is an EMT-inducing transcription factor (EMT-TF) (52). As a major propeller of EMT in cancer progression and metastasis (53, 54), TGF-β can initiate tumorigenesis by activating EMT-type III initiation in epithelial cell compartments at the early stage of cancer development (55, 92). Gastric fibroblasts activated by H. pylori promote normal gastric epithelial cells to precancerous phenotype, and promote EMT by regulating TGFβ R1/R2-dependent signaling (55). The HH, Wnt, and Notch signaling pathways can interact with TGF-β pathway and induce EMT progression (93–97).

Collectively, persistent H. pylori infection increases the differentiation of CAFs, which propel EMT through NF-κB, STAT3, and TGF-β. As CAFs play key roles in the gastric microenvironment, targeting CAFs might be a potential strategy to improve the prognosis of patients (98, 99).

Immature myeloid (progenitor) cells (IMCs) do not mediate immunosuppression in healthy individuals. However, chronic inflammation, infections, and autoimmune diseases impair IMC differentiation and decrease peripheral myeloid cells numbers, resulting in more myelopoiesis (100–103). This eventually results in myeloid-derived suppressor cells (MDSCs) accumulation and immunosuppression (102, 104). MDSCs mediate immune suppression by inducing immunosuppressive cells (105), blocking lymphocyte homing (106), producing reactive oxygen and nitrogen species (107, 108), exhausting critical metabolites for T cell function (109), expressing negative immune checkpoint molecules (110).

Interactions between H. pylori and MDSCs are important in gastric immune microenvironment. On one hand, H. pylori can induce the differentiation of myeloid cell differentiation factor Schlafen 4 (SLFN4⁺) MDSCs (56, 58). This factor marks a subset of MDSCs in the stomach during H. pylori-induced spasmolytic polypeptide-expressing metaplasia (SPEM) (57). During chronic H. pylori infection in mice model, a subset of HH-Gli1-dependent immune cells is recruited to the gastric epithelium, and polarizes into SLFN4⁺ MDSCs. Overexpression of the SHH ligand in infected WT mice accelerates SLFN4⁺ MDSCs differentiataion in gastric corpus (57). Furthermore, H. pylori can stimulate plasmacytoid dendritic cells to secrete IFN-α through toll-like receptor 9-myeloid differentiation factor 88-interferon regulatory factor 7 (TLR9-MyD88-IRF7 pathway) (58). Differentiated SLFN4⁺ MDSCs inhibit gastric inflammatory response induced by H. pylori and suppress T cell function (56–59). Persistent immune dysregulation then favors intestinal metaplasia and neoplastic transformation, which leads to immune disorders and tumor progression.

Several markers, such as MiR130b, apoptosis signal-regulating kinase 1 (ASK1), interleukin 22 (IL-22), programmed death-ligand 1 (PD-L1), and Krüppel-like factor 4 (KLF4) play regulatory roles in the interactions between H. pylori and MDSCs. MiR130b produced by SLFN4⁺ MDSCs suppress T cells function and promote H. pylori-induced metaplasia (59). ASK1 deficiency promotes a Th1-dependent immune response and recruits immature Gr-1⁺Cd11b⁺ MDSCs with H. pylori infection. This could lead to the development of gastric atrophy and metaplasia (25, 60). Moreover, IL-22 secreted by polarized Th22 cells induced by H. pylori can stimulate CXCL2 production from gastric epithelial cells. This causes CXCR2⁺ MDSCs migration to gastric mucosa, where they produce proinflammatory proteins and suppress Th1 cell responses, contributing to the development of H. pylori-associated gastritis (61). PD-L1 upregulation on the surface of gastric epithelial cells at the early stage of H. pylori infection (62) promotes tumor infiltration of MDSCs (63) and then lead to anti-PD-1/PD-L1 treatment resistance (64). KLF4 is an evolutionarily conserved zinc finger transcription factor and key regulator of diverse cellular processes (111–113). Helicobacter pylori and its virulence factor CagA can influence KLF4 expression. The transduction of CagA or infection with H. pylori downregulates KLF4 expression by inducing CXCL8 expression, and low KLF4 expression further upregulates CXCL8 expression (65). Increased CXCL8 expression promotes MDSCs recruitment to tumors as well as tumor growth, and creates an immunosuppressive microenvironment conducive to resistance against immune response (65–67).

A high abundance of MDSCs in patients correlate with more advanced GC and a poor prognosis (114, 115). MDSCs infiltration induced by H. pylori mediates immunosuppression, immune dysfunction, gastric tumorigenesis, and reduces the effect of chemotherapy and immunotherapy (63). The possibility that combining immunotherapy or chemotherapy with MDSC-targeting therapy might overcome drug resistance and improve prognosis warrants investigation (116–118).

The 5-year survival rate of advanced GC patients is <30%. Although platinum-fluoropyrimidine combination chemotherapy is the standard first-line treatment for advanced GC, its low complete response rate and severe adverse reactions have limited its application (63, 166). Novel effective therapies are urgently required. For example, PD-1 inhibitor pembrolizumab received accelerated approval from the US Food and Drug Administration (FDA) in 2017 to treat recurrent advanced or metastatic gastric or gastroesophageal junction adenocarcinomas expressing PD-L1 (63, 167–169).

Helicobacter pylori is a class I carcinogen associated with GC (170–172). The overall survival of GC diagnosis is reported to be higher for patients with H. pylori infection (17). Helicobacter pylori infection induces PD-L1 expression and MDSC infiltration that mediate immune escape. HH signaling activated by H. pylori infection induces PD-L1 expression and tumor cell proliferation in GC, resulting in cancer cell resistance to immunotherapy (150). In addition, Helicobacter pylori and its virulence factors can act as antigens or adjuvants to enhance tumor immunity.

Helicobacter pylori virulence factors, such as CagA, VacA, blood-group antigen-binding adhesin gene (BabA), and H. pylori neutrophil-activating protein (HP-NAP), can act as antigens or adjuvants to enhance tumor immunity. The stimulation of autoantibodies during antigen processing and presentation and subsequent T-cell activation and proliferation improves the host immune status, which can kill cancer cells and even suppress metastasis (151). Moreover, H. pylori DNA vaccines encoding fragments of CagA, VacA, and BabA can induce Th1 shift to Th2 response in immunized BALB/c mice, which mimics the immune status of GC patients with chronic H. pylori infection. Stimulated CD3⁺ T cells inhibit the proliferation of human GC cells in vitro, and the adoptive infusion of CD3⁺ T cells inhibits the growth of GC xenografts in vivo (152).

HP-NAP is a major virulence factor in H. pylori infection and colony formation, and it can also act as a protective factor (173, 174). As a Toll-like receptor-2 (TLR2) agonist, HP-NAP can bind to TLR2 of neutrophils (161, 175). Furthermore, HP-NAP promotes the maturation of DCs with Th1 polarization and improves migration of mature DCs. Stimulating neutrophils and monocytes by HP-NAP induces IL-12 and IL-23 expression, thus shifting antigen-specific T cell responses from the Th2 to the Th1 phenotype which characterized by abundant IFN-γ and TNF-α expression (153). Vaccination with HP-NAP A subunit (NapA) promotes Th17 and Th1 polarization. Such vaccines have potential effects as an anti-H. pylori oral vaccine candidate and a mucosal immunomodulatory agent, which could be used in antitumor strategies (154).

In addition to GC, the influence of H. pylori on other tumor immunotherapies is also paid much attention recently. Helicobacter pylori infection might disrupt the immune system and exert detrimental effects on the outcomes of cancer immunotherapies (19).

Helicobacter pylori seropositivity could reduce anti-PD-1 immunotherapy effect in non-small cell lung cancer (NSCLC) patients. Helicobacter pylori infection partially blocks the activities of ICIs and vaccine-based cancer immunotherapies. Helicobacter pylori suppresses the innate and adaptive immune responses of infected hosts and inhibits antitumor CD8⁺ T cell responses by altering the cross-presentation activity of DCs (19). In contrast, a significantly high proportion of tumor-infiltrating T lymphocytes in H. pylori-positive de novo diffuse large B-cell lymphoma (DLBCL) patients preliminarily indicates a benign TME. Inflammation induced by H. pylori confers persistent activation of autoimmune Th cells, which would explain the benign TME (155). More researches are necessary to elucidate how H. pylori infection status influences the effects of tumor immunotherapies.

The immunomodulatory activity and potential applications of NAP in tumor immunotherapy have been investigated. Recombinant HP-NAP with the maltose-binding protein of Escherichia coli (rMBP-NAP) can mediate T helper lymphocytes differentiation into the Th1 phenotype and significantly increase the number of CD4⁺ IFN-γ-secreting T cells. This induces antitumor effects through a TLR-2-dependent mechanism in subcutaneous hepatoma and sarcoma mice model (156). rMBP-NAP can significantly increase peripheral blood mononuclear cells (PBMCs) that secrete IFN-γ, and prominently increases the cytotoxic activity of PBMCs derived from lung cancer patients (157). Treatment with rMBP-NAP restricts the progression of metastatic lung cancer in mice model by triggering antitumor immunity (158). A therapeutic nanocomplex of HP-NAP altered the production rate of cytokines and increase tumoricidal activities of the immune system, leading to decreased breast tumor growth in mice (137). Local administration of HP-NAP inhibits tumor growth by triggering tumor cell necrosis in bladder cancer mice model (159). Recombinant HP-NAP has potential effects as an adjuvant in DC-based vaccines for treating melanoma (160).

Because of its ideal immunogenicity, NAP has recently been applied as an immune adjuvant to enhance the antitumor immune response. When combined with oncolytic viruses (OVs), HP-NAP can activate the immune response. The intratumoral administration of adenovirus armed with secretory HP-NAP can improve the median survival rate of nude mice xenografted with neuroendocrine tumors (161). A recombinant vaccinia virus (VV) neuroblastoma-associated antigen disialoganglioside mimotope (GD2m)-NAP significantly improved therapeutic efficacy. Helicobacter pylori-NAP might help to overcome virus-mediated suppressive immune responses, resulting in improved anti-GD2 antibody production and a better therapeutic outcome (164, 165). Moreover, recombinant measles virus (MV)-NAP-urokinase-type plasminogen activator receptor (uPAR) can improve immunotherapeutic effects on glioblastoma with a better tumor prognosis and increased susceptibility to CD8⁺ T cell-mediated lysis. Overall, HP-NAP represents a potential immunostimulatory agonists which can boost the immunogenicity of OVs and enhance ICIs effects (162, 163).

In conclusion, H. pylori and its virulence factors could be closely related with personalized treatment strategies during tumor immunotherapies. The mechanisms of H. pylori infection in tumor immunotherapies requires further elucidation, and the translation of research findings to clinical applications should be accelerated.