Most immune cells are present within the invasive margins and central zone of tumors (103). However, macrophages often comprise the dominant immune cell population in TIME as they include the first pro-inflammatory innate immune cell responders in the chronic inflammatory environment, which later polarize to tumor-supportive immunosuppressive M2 or TAMs (104–106). M1 to M2 macrophages polarization occurs in response to low glucose, glutamine, and FAs availability in a nutrient competitive TME. M2 polarization is further supported by increased TGF-β, IL-4, IL-5, IL-6, and IL-10 availability in the TME ( Figure 3 ). TAMs support tumor growth, survival, proliferation, and metastasis by supporting tumor angiogenesis, chemoresistance, and immunosuppression (107–110). Hence, understanding their immunometabolic reprogramming in TME or TIME is warranted.

For example, M1 macrophages depend on aerobic glycolysis to infiltrate the hypoxic TME and exert their pro-inflammatory and anti-tumor actions (98, 111). The IL-4-dependent M1 to M2 macrophage polarization supports OXPHOS through interferon regulatory factor 4 (IRF4) and mTORC2 activation (112). However, IL-4-mediated M2 macrophage polarization does not require immunometabolic reprogramming to FAO (113). Also, the IL-4-mediated M1 macrophage polarization to M2 phenotype only occurs only when NO^· generation is blocked due to the dysregulated mitochondrial function (114, 115). TME/TIME and IL-4 synergistically increase protein kinase RNA-like ER kinase (PERK)-signaling cascade in macrophages to promote immunosuppressive M2 transition, activation, and proliferation (116). PERK activation induces phosphoserine aminotransferase 1 (PSAT1) and serine biosynthesis via activation transcription factor-4 (ATF-4). The increased serine biosynthesis supports an enhanced mitochondrial function and α-ketoglutarate (α-KG) synthesis required for Jumonji domain-containing protein-3 (JMJD3)-dependent epigenetic modification (116). On the other hand, PERK activity loss impedes mitochondrial respiration and FAO crucial for M2 macrophages. Hence, the immunometabolic reprogramming among macrophages depends on stimulus, tissue environment, and mitochondria health. TME and associated TIME are complex due to severely altered tumor cell phenotype, function, and different oncometabolites.

The hypoxic and glucose-deprived TME induces regulated in development and DNA damage response 1 (REDD1) on TAMs that suppresses mTORC1 signaling and associated glycolysis ( Figure 3 ) (117, 118). The increased levels of other oncometabolites, including lactate and succinate in TME, further support the M1 to M2 macrophages or TAMs polarization ( Figure 3 ) through different mechanisms, including yes-1 associated protein (YAP) and NF-κB inhibition via G protein-coupled receptor 81 (GPR-81)-mediated signaling (119, 120). Macrophages in TIME or TME uptake lactate via increased expression of monocarboxylate transporter 1 (MCT1) that increases OXPHOS and FAO to generate M2 macrophages or TAMs ( Figure 3 ) (121, 122). There are three types of M2 macrophages (M2a, M2b, and M2c), which secrete common immunosuppressive cytokines (TGF-β and IL-10) and chemokines to support tumor growth ( Figure 3 ) (123). Also, TAMs promote angiogenesis via secreting VEGF and other angiogenesis-promoting factors to support tumor growth, proliferation, and metastasis ( Figure 3 ) (117–119).

Cancer cells secrete M-CSF that promotes fatty acid synthase (FASN) activity in myeloid cells, including TAMs (124). FASN in TAMs via peroxisome proliferator-activated receptor (PPAR)β/δ activation promotes increased IL-10 synthesis and release. IL-10 promotes immunosuppression, angiogenesis, tumor growth, and metastasis ( Figure 3 ). Also, tumor-cell-produced lipids simultaneously orchestrate M1 to M2 macrophage polarization and survival in TME or TIME via inducing ER stress response by reshuffling lipid composition and saturation on the ER membrane ( Figure 3 ) (125). Furthermore, ER stress induces inositol-requiring enzyme 1 (IRE1, an endoplasmic reticulum stress sensor)-mediated spliced X-box-binding protein 1 (XBP1) production and STAT3 activation. The IRE1 production and STAT3 activation support M2 macrophage polarization and immunosuppressive TIME development (125–127). Hence, conditions favoring M2 macrophage transition exert a strong push towards OXPHOS in TAMs, which damages their mitochondria, producing increased ROS ( Figure 3 ) (128). The increased ROS production further supports hypoxia and angiogenesis in TME, adding to tumor growth and metastasis. ROS further suppresses the antitumor action of infiltrated T cells ( Figure 3 ). FAO-dependent ROS generation activates NLRP3 inflammasome to release IL-1β from TIME M2 macrophages, supporting tumor cell migration and metastasis ( Figure 3 ) (129). Also, exosomes released from tumor cells in TME support the M1 to M2 macrophage transition via activating NLRP6/NF-κB pathway to support immunosuppressive TIME and cancer cell metastasis (130). Arginase 1 (Arg1) expression in TAMs lowers the L-arginine availability to T cells in TME or TIME. It recruits immunosuppressive T_regs to support tumor growth and development ( Figure 3 ) (131). The simultaneous Arg1 and inducible nitric oxide synthesis (iNOS) expression in TAMs (M1/M2 phenotype) at low arginine concentration may favor ROS and RNS production that may inhibit antitumor T cell function in TIME (132–134).

Also, TAMs show a decreased receptor-interacting protein kinase 3 (RIPK3, a central factor in necroptosis) that inhibits caspase 1 (CASP1)-mediated cleavage of PPAR-γ to support FAO (135). The M2 macrophage polarization also involves increased glutamine catabolism (glutaminolysis) and UDP-GlcNAc-associated modules (136). The increased glutaminolysis replenishes the TCA cycle in immunosuppressive TAMs (137). Thus, the glutamine deprivation or N-glycosylation inhibition decreases M2 polarization and CCL22 production and promotes their polarization to M1-like macrophages (136, 138). The indoleamine 2,3-dioxygenase (IDO) expression in M2 macrophages also increases, which depletes local tryptophan via generating immunosuppressive kynurenine metabolites (139, 140). Hence, immunometabolic reprogramming among TAMs (highest in number among TIME immune cells) gives them an immunosuppressive phenotype. These immunosuppressive macrophages suppress other immune cells, including T cells through direct interaction or secreting immunosuppressive metabolites, switching their immunometabolism to immunosuppressive or exhausted phenotype (141–145).

Tumor cells and immune cells release several factors, including TNF-α, IL-8, IL-1α, CXCL1, CXCL2, and CXCL5 to stimulate neutrophil chemotaxis to the TME (146, 147). Although only mature neutrophils leave bone marrow (BM) for the circulation and target organs, TIME also harbors immature neutrophils ( Figure 4 ) (146, 148). At initial stages, neutrophils exert antitumor action but become tumor and metastasis supportive later. They can be classified as antitumor N1 neutrophils that are supported by IFN-β and hepatocyte growth factor (HGF) and protumor N2 neutrophils that are supported by TGF-β and G-CSF (147). The complex immunological functions of neutrophils and their targeting in cancer are discussed elsewhere (147, 149–151).

In cancer-bearing mice, neutrophils leaving the BM show more spontaneous migration than in typical tumor-free mice (152). For example, these neutrophils lack immunosuppressive action, having increased OXPHOS and glycolysis rate than neutrophils of typical tumor-free individuals ( Figure 4 ). The aggravated autocrine ATP signaling supports the increased neutrophil infiltration to TIME via purinergic receptors ( Figure 4 ) (152). The hypoxic environment in the TME or TIME increases HIF-1α and HIF-2α levels (65). HIF-1α increases neutrophil survival via supporting glycolysis (OXPHOS is not crucial for neutrophils) at initial stages, creating a chronic pro-inflammatory environment to support tumor progression (153). At the same time, HIF-2α increases the lifespan of pro-inflammatory neutrophils called tumor-associated neutrophils (TANs) (154). Also, the PPP in neutrophils supports increased ROS generation that induces apoptotic cell death among infiltrated T cells to support further a tumor suppressive TIME ( Figure 4 ) (155, 156). PPP is also involved in the neutrophil extracellular trap (NETs) formation or NETosis by fueling NADPH oxidase with NADPH to produce superoxide that supports cancer metastasis (157). However, immunosuppressive mediators, including TGF-β released at later stages of the tumor, polarize antitumor N1 TANs to pro-tumor N2 TANs (158–160). Also, the glutamine and proline uptake in immature low-density neutrophils (iLDNs) supports their pro-metastasis action inducing NETosis under hypoxic and glucose-deprived conditions ( Figure 4 ) (161, 162). NETs promote cancer growth, progression, and metastasis and provide a protective shield to them through different mechanisms discussed somewhere else (163).

MDSCs are well-known immunosuppressive innate immune cells found only in pathological conditions, including cancer (164–166). They are of two types (1) monocytic-MDSCs or M-MDSCs, and (2) polymorphonuclear-MDSCs or PMN-MDSCs (167). Hence, MDSCs are the pathological phenotypes of neutrophils and monocytes accumulating in pathological lesions, including TME or TIME (164, 165). PMN-MDSCs of patients with cancer also show an increased spontaneous migration characteristic and are present at very early cancer stages (152, 168). Different chemokines, including IL-8 (CXCL8) and CXCR4 chemoattract (in response to miR-494) MDSCs to TME or TIME ( Figure 5 ) (169–171). They secrete different immunosuppressive cytokines, including IL-10 and TGF-β, responsible for their immunosuppressive function to support tumor growth, proliferation, neoangiogenesis, and metastasis (170, 172). MDSCs also secrete vascular endothelial growth factor (VEGF)-A, fibroblast growth factor (FGF), and Bv8 (prokineticin or PK), and different MMPs to promote tumor growth and metastases ( Figure 5 ) (173, 174).

MDSCs depend on AMPK and FAO for their immunosuppressive function (175, 176). Glutamate or L-glutamine (L-Gln) taken by MDSCs in TME or TIME is oxidized in an AMPK-dependent manner to support their immunosuppressive function by regulating the TCA cycle ( Figure 5 ) (177). Even tumor-infiltrated/associated MDSCs (T-MDSCs) synthesize their L-Gln and with increased transglutaminase (TGM) expression that supports their immunosuppressive function and tumor metastases (178, 179). T-MDSCs show an increased FAO, OXPHOS, and glycolysis due to an increased lipid/FAs content in TME or TIME ( Figure 5 ) (176). However, the increased FAs in TME or TIME promote FAO in MDSCs via CD36-mediated FA uptake, and FAO inhibition suppresses their immunosuppressive function in TME (176, 180, 181).

The fatty acid transport protein 2 (FATP2) on PMN-MDSCs through arachidonic acid (AA) uptake and prostaglandin E2 (PGE2) synthesis also support the immunosuppressive function of MDSCs ( Figure 5 ) (182, 183). Furthermore, the PGE2-mediated negative feedback loop FATP2 and receptor-interacting protein kinase 3 (RIPK3, A negative regulator of FATP2) promotes PMN-MDSCs’ immunosuppressive function (184, 185). GM-CSF controls the FATP2 overexpression on PMN-MDSCs in TIME via STAT5 activation. TME or TIME hypoxia increases the immunosuppressive function of T-MDSCs by increasing the HIF-1α level ( Figure 5 ) (186, 187). Furthermore, HIF-1α, along with promoting their immunometabolic reprogramming to immunosuppressive phenotype, also increases the PD-L1 expression that suppresses the cytotoxic and immune-promoting functions of CD8⁺ and CD4⁺T cells in TIME (188). A high lactate level in TME increases the survival and proliferation of immunosuppressive MDSCs through G protein-coupled receptor 81 (GPR81)/mTOR/HIF-1α/STAT3 pathway (189–191). Also, the increased TME lactate level increases the number and proliferation of MDSCs, which inhibit NK cell cytotoxicity (NKCC) ( Figure 5 ) (190). Hence, hypoxic TME or TIME supports MDSCs’ immunometabolic reprogramming to FAO to favor their tumor and metastasis-supportive function.

DCs are potent antigen-presenting cells (APCs), which play a crucial role in generating and regulating immune response via recognizing different pathogens and inflammogens and presenting antigens to adaptive immune cells (T and B cells) (192). They also serve a part of first responding innate immune cells against cancer via antigen presentation despite constituting a rare immune cell population (CD103⁺DCs) within TME or TIME capable of activating CD8⁺T cells ( Figure 6 ) (193, 194). Conventional DCs (cDCs) at early malignancy recognize dying tumor cells and migrate to draining lymph nodes (DLNs) to present tumor antigens to CD4⁺ and CD8⁺ T cells (195, 196). For example, type 1 cDCs (cDC1s) prime cytotoxic CD8⁺T cells, and type 2 cDCs (cDC2s) activate antitumor helper CD4⁺T cells (197–199). The antitumor action of cDC1s in TIME depends on NK cells as they release cDC1 chemo-attractants CCL5 and XCL1 to bring them in ( Figure 6 ) (200, 201). However, the prostaglandin E2 (PGE2) release by tumor cells in TME or TIME suppresses NKCC and the production of cDC1 chemo-attractive chemokines ( Figure 6 ). Thus, cDC1s lose their antitumor function due to the evasion of the NK cell-cDC1 axis and other immune cells with tumor growth. Furthermore, cDC2s (CD11b⁺DCs) in tumor DLNs also express PDL-1 and suppress T cell-mediated antitumor immunity ( Figure 6 ) (202, 203). Additionally, monocyte-derived DCs (mo-DCs) with pro-inflammatory properties comprise another type of DCs populating tumors (198). Also, the plasmacytoid DCs (pDCs) in tumor DLNs release IDO that directly activates mature T_regs to create an immunosuppressive TIME ( Figure 6 ) (204). The details of immunologic and immunoregulatory functions of DCs in TME or TIME are mentioned elsewhere (205–208). We will focus their immunometabolic reprogramming in TME or TIME.

Under a steady state, DCs depend on OXPHOS for their energy demand to maintain immune homeostasis (209). For example, bone marrow-derived DCs (BMDCs) depend on FAO for OXPHOS to meet the energy demand, but the involvement of FAO for OXPHOS in cDCs and pDCs is not yet clear (192, 209). FAO and OXPHOS do not provide the maximum threshold for DCs to secrete cytokines and activate T cells to create a pro-inflammatory environment. The pro-inflammatory PRRs, like toll-like receptor-4 (TLR-4) stimulation, reprograms DC immunometabolic state from OXPHOS to glycolysis within minutes, like other myeloid immune cells (209–211). The shift from OXPHOS to glycolysis induces their antigen presentation potential through increased major histocompatibility complex (MHC)-I and -II expression, co-stimulatory molecules (CD80 and CD86), and cytokine synthesis and release. Although increased glucose uptake by DCs during the early stages of activation is accompanied by lactate production, this does not reflect a commitment to Warburg metabolism as a mechanism for ATP production because, during this time, ATP is provided by OXPHOS (211). Instead, glycolysis fulfills the citrate needs of DCs is filled by glycolysis (211). The export of citrate from the mitochondria into the cytoplasm through the citrate transporter SLC25A is significant for fueling FAS required for activated DCs to increase the size of critical organelles (Golgi bodies and endoplasmic reticulum or ER) involved in protein synthesis and secretion. Intriguingly, the enlargement of these compartments co-occurs with increased gene expression downstream of TLRs but is regulated post-transcriptionally by increased glycolytic flux. This is controlled by the Akt-dependent phosphorylation and subsequent activation of hexokinase II (essential to catalyze the first step of glycolysis) (211).

The Akt activation involves TANK-binding kinase 1 (TBK1)/I-kappa-B kinase epsilon (IKKϵ), activation downstream of RIG-I–like receptor (RLR), indicating that the rapid glycolysis is a typical response to any innate immune recognition by DCs. This Akt activation occurs regardless of PI3K or mTOR (two canonical Akt upstream activators) inhibition (210, 211). Different PRRs, including TLR2, TLR6, TLR9, Dectin-1, and -2 activation, induce immunometabolic reprogramming to glycolysis in DCs that governs their inflammatory status and motility (212, 213). Notably, early glycolysis induction in DCs occurs independently of their pro-inflammatory phenotype. This allows DCs to rapidly respond metabolically to these danger signals originating in the TME (211).

DCs fail to mature in the absence of OXPHOS to glycolysis transition. Also, DCs showing weak inflammatory response lack long-term glycolytic reprogramming requiring increased glycolytic gene expression (212). Thus, a prolonged and increased glycolysis enzymatic gene expression is crucial for maintaining pro-inflammatory DCs and their migration. Also, DCs utilize pre-existing glycogen stores to support shifting from OXPHOS to glycolysis during their inflammatory stimuli to drive their TLR-dependent activation (214). The glycogenolysis inhibition attenuates TLR-mediated DC maturation and impairs their ability to act as APCs. Therefore, it is likely that even weak inflammatory signals can induce early glycolytic reprogramming through glycogenolysis without a significant and prolonged gene transcription crucial for glycolysis reprogramming. However, this is not true for other myeloid cells, including macrophages, which depend on external glucose supply through glucose transporter 1 (Glut1) upon inflammatory stimuli. Thus, only strong pro-inflammatory signals can induce prolonged inflammatory phenotype and DC motility in LNs.

IL-10 and AMP-activated protein kinase (AMPK, the central regulator of catabolic pathways and OXPHOS) inhibit glycolysis (215). The FAS inhibition enhances DCs’ capacity to activate allogeneic and Ag-restricted CD4⁺ and CD8⁺ T cells and induce CTL responses (216). Further, FAS blockade increases DC expression of Notch ligands and enhances their ability to activate NK cell immune phenotype and IFN-γ production. ER stress enhances DC’s immunogenic function upon FAS inhibition, accounting for its higher immunogenicity (216). Conversely, the ER stress lowering by 4-phenylbutyrate (4-PBA) suppresses their increased immunogenic action due to FAS inhibition. TLR7/8 stimulation with promoter-associated RNA (pRNA) increases FAO and OXPHOS in human mo-DCs due to branched-chain alpha-keto acid dehydrogenase complex E1-alpha subunit (BCKDE1α) phosphorylation in a phosphatase and tensin homolog (PTEN)-induced putative kinase 1(PINK1)-dependent manner. Interestingly, inducing PINK1 activity in tolerogenic DCs stimulates FAO and renders them immunostimulatory (217).

Tumor-associated DCs (TADCs), like tumor-associated T cells, also face the harsh nutrient-deficient environment that activates AMPK, inhibiting the immunometabolic reprogramming from OXPHOS to glycolysis. For example, AMPK supports OXPHOS by upregulating proliferator-activated receptor γ co-activator (PGC-1α) that binds to PPAR-γ to promote mitochondrial biogenesis, oxidative metabolism and antagonize anabolic metabolism (218, 219). Thus, TADCs lose their APC properties and migration capacity to DLNs to prime and induce a robust adaptive immune response against tumor antigens. The recognition of exogenous adenosine monophosphate (AMP) by adenosine A_2b receptor expressed on DCs, including TADCs, upregulates their pro-tumorigenic functions, including angiogenesis via releasing VEGF, TGF-β, and creating an immunosuppressive environment through releasing IL-10 and expressing cyclooxygenase-2 (COX-2) and IDO (220–223). IDO (IDO1 and IDO2) activity metabolizes tryptophan (an essential amino acid) into kynurenine (224). Thus, the tryptophan depletion activates a stress response kinase called general control non-derepressing 2 (GCN2) in T cells that inhibits their proliferation and biases naïve CD4⁺T cells to develop into FoxP3⁺T_regs (225–227). Also, the kynurenine and other metabolites bind to the aryl hydrocarbon receptor (AhR) on T cells, promoting their differentiation to T_regs along with supporting the immunosuppressive macrophage and DC phenotype (226, 228–230).

Catabolism of pre-existing glycogen in DCs is crucial to initiate glycolysis independent of external glucose supply in response to the TLR activation (214). However, in TME or TIME, the continuous TLR signaling, including the TLR9 activation in response to the host cell-derived DNA creates an immunosuppressive TIME due to the increased IDO expression (231–233). Furthermore, TLR9 ligand CpG ODN 2006 is a poor adjuvant to induce CD8⁺T cells responsible for clearing tumor cells (234). This may be due to the poor DCs activation or their suppression through IDO generation. Further studies are required in this direction. The increased AMPK expression in TADCs also transforms them into tolerogenic DCs due to increased FAO and OXPHOS (210, 235). Furthermore, the aberrant lipid accumulation in TADCs due to the transport of extracellular lipids via macrophages scavenger receptor 1 (MSR1) diminishes their antigen-presenting capacity that suppresses their adaptive immune activation property to fight against tumors (236, 237). Also, the tumor-released Wnt5 molecule triggers PPAR-γ activation through β-catenin, which activates FAO by upregulating carnitine palmitoyltransferase-1A (CPT1A, a fatty acid transporter) in TADCs and induces a tolerogenic phenotype and secrete IDO to create an immunosuppressive TIME by upregulating T_regs (238, 239). Furthermore, the Wnt5 also blocks the immunometabolic shift to glycolysis in TADCs and induces an increased FAO. In addition, β-catenin induces vitamin-A metabolism in TADCs and FAO to produce retinoic acid (RA), further promoting T_regs generation to create an immunosuppressive TIME (240) Thus, TME or TIME DCs also become potent immunosuppressive immune cells and lose their antigen presentation characteristics to further support adaptive immunity against tumors due to their immunometabolic reprogramming supporting their survival but not potent immune function.

ILCs are a relatively new class of immune cells, which phenotypically appear as adaptive lymphoid cells. However, they are lineage negative and do not express antigen-specific receptors encoded by rearranged genes, including T cell or B cell receptors (TCRs or BCRs). ILCs also do not show V(D)J recombination required for somatic hypermutation (SHM)/recombination, like T and B cells (241). However, they respond to various immunogenic stimuli, including pathogens, to mounting a pro-inflammatory immune response. Additionally, they are highly localized to mucosal surfaces (gastrointestinal, reproductive, and respiratory tracts). The details about different types of ILCs, including ILC1s or group 1 ILCs (NK cells and helper ILC1s), ILC2s (group 2 ILCs, produce Th2 cytokines), and ILC3s (group 3 ILCs, include RORγt⁺ ILCs and lymphoid tissue inducer or LTi cells) inflammation and their interaction with adaptive immune cells have been discussed elsewhere (242–246).

ILCs increase in the circulation of patients with cancer compared to healthy controls, indicating that they also infiltrate TME or TIME of different cancers ( Figure 7 ) (247–251). Patients with a high number of circulating ILCs, including NK cells with great cytotoxic action, are less prone to develop cancer and metastasis (252–254). The ILC (NK cells, ILC1s, ILC2s, and ILC3s) infiltration into the TME at the early (premalignant) stage induces anti-tumor TIME to kill tumor cells through different mechanisms, including direct cytotoxic action and recruitment of different immune cells, including cytotoxic T cells, and eosinophils (255–259). The details of ILCs, including NK cells in early TME, have been discussed elsewhere (260, 261).

At later stages, NK cells infiltrating TME become less cytotoxic ILC1s (inefficient in controlling the growth and metastasis of tumor cells) in the presence of TGF-β secreted by tumor cells and other immunosuppressive immune cells (262–264). TGF-β also downregulates eomesodermin (EOMES) or T-box brain protein 2 (Tbr2) expression ( Figure 7 ) (262). EOMES and T-box protein in T cells (T-bet) are crucial for NK cell development, maturation, and cytotoxic function (265–267). Also, EOMES is crucial for invariant NK (iNK)T cell development and differentiation in the thymus and their differentiation to memory-like KLRG1⁺iNKT cells in the periphery (268). iNKT cells facilitate the potent anticancer cytotoxic action of CD8⁺T cells by presenting different lipid and glycolipid antigens to expressed MHC class I-like molecule CD1d, in addition to direct killing (269, 270). iNKT cells also release IFN-γ that further supports tumor cell killing by NK cells (270). Hence, it will be novel to study the impact of TGF-β on iNKT cell development and function in TME or TIME, which depends on EOMES expression. Furthermore, TGF-β in TME also reprograms otherwise antitumor ILC3s to tumor-promoting regulatory ILC3s (ILC_regs) and secrete IL-10 (271).

IL-25, an IL-17 cytokine subfamily member in TME or TIME, transforms inflammatory ILC2s (iILC2s) to natural ILC2s (nILC2s) or ILC3-like cells to create an innate tumor-permissive microenvironment through activating ILC2s via inducing IL-17 expression (272, 273). iILC2s have a low RORγt expression, but nILC2s do not (274). Also, these tumor infiltrating ILC2s are highly IL-25R⁺ (273). These nILC2s secrete large amounts of IL-5 and IL-13 (Th2 cytokines), creating an anti-inflammatory or immunosuppressive TIME (272). However, IL-25 exerts a tumor regulatory role through different mechanisms, including eosinophil and B cell infiltration, apoptosis, and Th2 cytokines secretion in TME to create an immunosuppressive TIME (275). The therapeutic blockade of IL-25R in colorectal cancer (CRC) lowers the tumor burden and activates an anti-tumor immune response in mice (273). These ILC2s join IL-25R⁺ MDSCs to create an immunosuppressive TIME in different cancers (276–278). Another study has shown that blocking IL-25 (released from gastrointestinal tuft cells) suppresses gastric cancer in mice, and the ILC2 axis, which is responsible for immunosuppressive IL-13 release (279). IL-33 (a member of IL-1 cytokine family) also promotes tumor survival and progression through different mechanisms, including T_regs functional stabilization (280, 281). Also, IL-33 exerts tumor supportive action via regulating PPAR-γ-mediated IL-4, IL-13, and IL-15 (Th2 cytokines) release from ILC2s ( Figure 7 ) (282). Thus, antitumor functions of ILCs, including NK cells, ILC2s, and ILC3s, reprogram to tumor-promoting immune activity governed by their immunometabolic reprogramming.

ILCs, including NK cells recruited to the nutrient-competitive TME with tumor cells, adjust their immunometabolic requirement affecting their antitumor immune function. For example, NK cells depend on glycolysis and OXPHOS for their energy requirement under immune homeostasis due to their limited energy or biosynthetic demand (283, 284). Under inflammatory conditions due to increased energy demand to perform a cytotoxic function and cytokine release, immunometabolic reprogramming shifts more towards aerobic glycolysis than OXPHOS, although an increase in OXPHOS also occurs like effector CD8⁺T cells that depends on mTORC1 activation (285–287). However, TME does not support their increased glucose demand to exert their antitumor action. For example, increased TGF-β in TME induces NK cell suppression through decreasing mitochondrial metabolism, including OXPHOS, which is crucial to maintain its high metabolic demand to maintain its antitumor activity (288). This process occurs independently of mTORC1 inhibition. However, TGF-β blocks IL-15-dependent NK cell proliferation and maturation via inhibiting mTOR signaling (289). Thus, it will be interesting to delineate factors responsible for a differential effect of TGF-β on mTOR signaling and dependent metabolic reprogramming, as mTORC1 signaling is crucial for NK cell maturation and proliferation in patients with metastatic cancers (290).

It is important to note that blocking TGF-β restores the anti-tumor function (including metastasis prevention) of NK cells via restoring their immunometabolic reprogramming crucial for cytotoxicity and IFN-γ release (288, 289). Additionally, lactate accumulation in TME also blocks NK cells’ OXPHOS via inducing mitochondrial dysfunction due to increased ROS release, making them energy deficient and causing their apoptosis ( Figure 7 ) (291). Thus, it will be interesting to delineate that to escape from apoptosis of TIME NK cells in the presence of TGF-β to polarize to less cytotoxic ILC1s having less energy demand to survive. Also, GM-CSF in TME converts immature NK cells to MDSCs, helping in cancer progression and metastasis (292).

The immunometabolic reprogramming of ILC2s is complex compared to other immune cells. For example, they use OXPHOS and branched-chain amino acids (valine, leucine, and isoleucine) to fuel their polarized mitochondria at their steady state during homeostasis (293). However, their developmental maturation depends on the HIF-1α-glycolysis axis (294). Hence, OXPHOS, branched amino acids, and glycolysis are crucial to maintaining ILC2s’ immune homeostatic function by regulating development and maturation. The release of IL-4, IL-6, and IL-13 (Th2 cytokines) from ILC2s is maintained by increased glutaminolysis, glycolysis, mTOR activation, and FAO (295, 296). However, they continue to OXPHOS through amino acid uptake to maintain their cellular fitness and proliferation (296). The increased FAO takes place in ILC2s of nutrient (glucose and glutamine)-deficient TME or TIME, which reprograms their antitumor function to tumor-promoting via releasing Th2 cytokines causing immunosuppression and angiogenesis ( Figure 7 ) (297).

Furthermore, the increased IL-33 level in TME or TIME promotes ILC2’s pro-tumor function via binding to its cognate receptor ST2, promoting temporary storage of externally acquired FA in lipid droplets to make cell membranes (298). These accumulating lipid droplets transform into phospholipids to promote ILC2s proliferation. An enzyme called diacylglycerol o-acyltransferase 1 (DGAT1) regulates this process. PPAR-γ, a key transcription factor, governs this immunometabolic reprogramming crucial for lipid uptake, metabolism, and ILC2 function (297, 298). For example, genetic deletion or pharmacological inhibition of PPAR-γ and DGAT1 in ILC2s blocks the IL-33-mediated cancer growth and metastasis (282). The IL-33-mediated optimal immunometabolic reprogramming in ILC2s also requires ROS, and its inhibition can prevent its tumor-promoting role by suppressing IL-5 and IL-13 release (299). Thus, TME supports immunometabolic reprogramming among ILC2s to create an immunosuppressive TIME that supports tumor growth and metastasis.

T cells are crucial adaptive immune cells, which have the potential to regulate the immune system through helper T (Th) cell phenotype and direct killing of tumor cells through their cytotoxic action (CD8⁺T cells) (102). The pro-inflammatory T cells (Th1, Th2, and Th17 phenotypes collectively called T effector (T_eff) phenotype) depend more on increased glycolysis than OXPHOSS (300, 301). The aerobic glycolysis controls T_eff function, including the IFN-γ release through binding the glycolysis enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) to AU-rich elements within the 3’ untranslated region (3’ UTR) of IFN-γ mRNA (302). Also, the lactate dehydrogenase A (LDHA) induction in T cells supports aerobic glycolysis but supports IFN-γ release or Th1 differentiation independent of 3’UTR through epigenetic mechanisms (303). In addition, in acidic TME (due to lactate accumulation), LDH converts lactate to pyruvate and lowers nicotinamide adenine dinucleotide (NAD⁺) levels. The decreased NAD⁺:NADH further blocks glycolysis in T cells ( Figure 8 ) (304). The increased lactate level in TME inhibits NAD⁺-dependent GAPDH and 3-phosphoglycerate dehydrogenase (PGDH) activity crucial for NADH reduction and serine production, important for T cell proliferation ( Figure 8 ) (304). Serine supplementation rescues T cell proliferation in high lactate TME.

LDHA maintains a high acetyl-coenzyme A (acetyl-CoA) level that promotes histone acetylation and IFN-γ transcription. LDHA deletion in T cells suppresses their IFN-γ-mediated pro-inflammatory action and induces their differentiation to FoxP3⁺ T_regs. FoxP3 expression in T_regs reprograms their immunometabolism to OXPHOS via suppressing Myc activity and glycolysis and increasing NAD⁺ oxidation ( Figure 8 ) (305). Due to this, T_regs resist highly acidic (lactate) TME and grow and proliferate (306). T_regs also take more lactate than T_effs to utilize it as a fuel for the TCA cycle or gluconeogenesis, which decreases their glucose need in the highly nutrient-competitive TME (305, 307). T_regs highly express lactate transporter, monocarboxylate transporter 1 (MCT-1), for lactate uptake in TME (307). Furthermore, TME lactate induces programmed cell death protein 1 (PD-1 or CD279) expression in T_regs, and PD-1 inhibition strengthens T_regs in TIME, causing treatment failure with PD-1-based checkpoint inhibitors (308, 309). However, a co-treatment with anti-PD-1 and a LDH inhibitor serves as a better anticancer treatment as this approach inhibits lactylation of Lys72 in MOESIN (a member of the ERM (ezrin, radixin, and moesin) proteins). The MOESIN lactylation inhibition improves MOESIN interaction with TGF-β receptor I and downstream SMAD (suppressor of mothers against decapentaplegic) family member 3 (SMAD3) signaling activating FoxP3 in T_regs (310).

T_reg differentiation in TME or TIME depends on the Basic leucine zipper transcription factor, ATF-like or BATF transcription factor (311). T_regs are highly dependent on FAO or β lipid oxidation and OXPHOS for their immunoregulatory function due to the lower Glut1 and higher AMPK expression (300, 301). The fatty acid binding protein 5 (FABP5, a cellular chaperone long-chain FAs) in T_regs regulates OXPHOS and immunosuppressive function by inducing the IL-10 release in response to the type 1 IFN (released in response to cGAS-STING signaling) in low lipid availability TME for immune cells ( Figure 8 ) (312). Hence, FABP5 is a gatekeeper for mitochondrial integrity modulating T_regs. Furthermore, FABP5 expression in pDCs in TME or TIME supports their tolerogenic role via supporting the generation of T_regs ( Figure 8 ) (313).

T_regs generation do not need mTOR kinase (314). Also, the CD36 expression increases in T_regs, supporting their survival and proliferation in TME or TIME via increased FA uptake ( Figure 8 ) (315). Furthermore, CD36 fine-tunes mitochondrial fitness via PPAR-β signaling to increase T_regs survival in a lactate-rich acidic TME by increasing OXPHOS ( Figure 8 ) (315, 316). On the other hand, CD36 expressed on CD8⁺ cytotoxic T cells increases oxidized lipids/low-density lipoproteins (oxLDLs) uptake that increases lipid peroxidation (LPO) ( Figure 8 ) (317). LPO activates p38 mitogen-activated protein kinase (p38MAPK) that induces CD8⁺T cell dysfunction through defective mitochondrial biogenesis in mTOR-independent signaling pathway governing their autophagy and glycolysis ( Figure 8 ) (317, 318). CD36-mediated lipid uptake by CD8⁺T cells in TME also causes their ferroptosis and LPO to cause their death and immunosuppression ( Figure 8 ) (319). Thus, CD36-mediated FA uptake determines T cell-dependent immunosuppressive TIME. Also, death/damage-associated molecular proteins (DAMPs) in TME promoting chronic inflammation can activate T_regs TLRs that, with FoxP3, balance mTORC1 signaling and glucose metabolism to control their proliferation and immunosuppressive function (320, 321). Hence, TME and TIME support T_regs for tumor growth and metastasis and induce resistance to chemotherapies and checkpoint inhibitors through immunometabolic reprogramming.

Th17 cells selectively express HIF-1α governed by mTOR signaling, a central regulator of cellular metabolism (301). HIF-1α is crucial for glycolysis induction and maintenance. The lack of HIF-1α in T cells at their differentiation stage reprograms them to develop into T_regs ( Figure 8 ) (301). The tumor-associated Th17 cells with low glycolysis capacity reprogram to FoxP3⁺T_regs ( Figure 8 ) (322). Thus, the local tissue environment, including metabolic status, is crucial determines T cell differentiation to their different phenotypes and function.

Low extracellular lactate promotes immune cell infiltration and proliferation at the premalignant stage, including T cells at the site to create a pro-inflammatory TIME to clear tumor cells. For example, CD8⁺T cells under physiologic normoxia utilize glycolysis to exert antitumor action, including IFN-γ release and cytotoxicity (323). The prolyl-hydroxylase (PHD) proteins are intrinsic oxygen-sensing molecules that promote T_regs growth and proliferation during hypoxia that develops at later stages of cancer (323). The T cell-specific internal deletion or pharmacological inhibition of PHD increases the antitumor action of tumor-infiltrating T cells. The increased energy demand among tumor cells reprograms their metabolism to increased glycolysis and creates a hypoxic TME. The increased glycolysis among tumor cells in TME increases extracellular lactate accumulation, which impairs the nuclear factor of activated T-cells (NFAT) activation and IFN-γ production by T and NK cells (324–326). This impairs the anticancer/tumor action of tumor infiltrating CD4⁺ and CD8⁺ T cells in the pro-inflammatory environment. For example, tumor infiltrating T cells in the glucose-deprived TME could not reprogram their immunometabolism to glycolysis, forcing them to rely on OXPHOS without exhibiting the T_eff phenotype that causes their mitochondrial depolarization and exhaustion (327–329). IL-12 treatment rescues T cell exhaustion by increasing their mitochondrial potential and reducing their dependence of glycolysis (330). Hence, IL-12 treatment prevents forced OXPHOS while maintaining the balanced glycolysis and OXPHOS to maintain their full effector function.

The increased PD-1-PD-L1 signaling (TAMs, cancer cells, and tolerogenic DCs express PD-1 and PD-L1), altered epigenetic reprogramming, and nutrient-deprived stressful TME through coordinating with the TCR signaling prove lethal to tumor-infiltrating CD8⁺T cells by altering their immunometabolic reprogramming (131, 327, 331, 332). Thus, low access to appropriate nutrients (glucose, glutamine, and lipids) imposes a significant barrier to T_effs via metabolic stress (333–336). For example, T cells under hypoxic conditions with limited glucose conditions exhibit mTORC1 signaling pathway inhibition, decreased antigen-induced expression of genes (including cell adhesion molecules, cell cycle progression), and CD8⁺T cell proliferation and effector function (335, 337).

The insufficient glucose level in TME or TIME induces apoptosis among T_{effs via} activating pro-apoptosis genes/proteins, including phorbol-12-myristate-12 acetate-induced protein 1(MAIP1/Noxa, a Bcl2 family protein) and Bcl-2-associated X protein (Bax), destabilizing myeloid cell leukemia 1 (Mcl1), an antiapoptotic Bcl-2 family protein (338). However, memory T_effs are not programmed to upregulate FAS, OXPHOS, and reductive glutaminolysis in limited glucose conditions, including TIME, which allows them to maintain their function in the nutrient-limited/depleted microenvironment (339). Thus, naïve T cells survive the nutrient-depleted TME or TIME but lose their effector function, but only memory T_effs survive and function in the environment. In addition, increasing FAO activity in CD8⁺T cells in TME or TIME can enhance their cytotoxic action as they show an increased PPAR-α signaling and FA catabolism, which preserves their cytotoxic action (340, 341). However, it should be noted that tumor progression also increases co-inhibitor expression on CD8⁺T cells, and PD-1 blockers delay tumor progression by affecting tumor-infiltrating lymphocyte (TIL) metabolism and function.

The cell motility is controlled by subtype-specific transporters called MCT1 (Slc5a12 and Slc16a1), specifically expressed on CD4⁺ and CD8⁺ T cells. The lactate accumulation suppresses the cytotoxic action of CD8⁺T cells and promotes the CD4⁺T cells switching to Th17 cells ( Figure 8 ) (324). Also, IL-2 (a cytokine critical for antitumor T cell function) signaling-mediated STAT5 activation becomes limited in a highly acidic TME (342). This further suppresses antitumor CD8⁺T cell function. The tumor-associated Th17 cells reprogram to FoxP3⁺T_regs in TME. The genetic targeting of LDHA in tumors decreases the pyruvate to lactate conversion restoring T and NK cell infiltration and their antitumor cytotoxic function (325). Pyruvate dehydrogenase kinase 1 (PDHK1) via inhibiting PDH determines the cytosolic lactate levels in T cells that varies with T cell subtype (343). For example, Th17 cells show a robust PDHK1 expression, whereas T_regs have it at an intermediate level and Th1 cells have very little PDHK1. Hence, TME promotes Th1 cells reprogramming to Th17 cells, then to T_regs under intratumoral high lactate level that also suppresses IL-2 signaling (342). The increase in the glutaminolysis in tumor cells also deprives infiltrated T cells of glutamine, further compromising their growth and proliferation ( Figure 8 ) (344). The glutamine-deficient TME reduces cytosolic α-KG in Th1 cells supporting their differentiation to T_regs (345). The glutaminase (a key enzyme involved in glutaminolysis) genetic deletion or glutamine uptake blockade in tumor cells increases TME glutamine and upregulates T cell infiltration (128, 346). The glutaminolysis is linked to polyamine biosynthesis via a Myc-dependent metabolic pathway in T cells (347). Hence, immunometabolic reprogramming among tumor-infiltrated T cells is governed by TME, including the hypoxia and lactate level.

HIF-1α during hypoxia induces the PDL-1 (CD274) expression in tumor cells, DCs, TAMs, and MDSCs to support immunosuppressive TIME (188). For example, PD-1⁺ CD8⁺T cells in TIME are most immunodysfunctional due to the mitochondria loss (348). The mitochondria loss affects their oxidative (TCA cycle, FAO, and OXPHOS) and membrane potential (ROS and ATP production) due to PPAR-γ coactivator 1α (PGC1α) loss, which programs mitochondrial biosynthesis by Akt signaling (348). B-lymphocyte-induced maturation protein 1 (BLIMP1) activation causes PGC1α loss. The PGC1α loss increases ROS production that, through phosphatase inhibition and the consequent activity of NFAT, promotes T cell exhaustion through mitochondrial dysfunction and loss (349–351). The mitochondrial mass loss in CD8⁺T cells of TIME correlates well with PD-1 expression. Thus, the PD-1/PDL-1 interaction in TIME suppresses T cell immune response governed by their metabolic stage or alters T cell immunometabolism responsible for immunosuppression (142). The increased lipolysis of endogenous lipids and FAO among PD-1⁺CD8⁺T cells continuously exposed to PDL-1-expressing cells survive longer to support the immunosuppressive TIME. These immunosuppressive CD8⁺T cells highly express CPT1A and the adipose triglyceride lipase (ATGL), the lipolysis marker glycerol, and the release of FAs (142). On the other hand, the T_regs PD-1 engagement with PDL-1 promotes FAO and mitochondrial OXPHOS to fuel their energy requirement in the presence of TGF-β (142, 352).

TGF-β suppresses PI3K-mediated mTOR signaling and inhibits glucose transporter and hexokinase 2 (Hk2) expression that favors OXPHOS in induced-T_regs (iT_regs). PD-1 reduces the TGF-β threshold for its immunosuppressive action, including the T_reg development and function in the TIME (353). Reduced TGF-β signaling via TGF-β type 1 receptor (TβR1) is crucial for T cell activation and associated immune response (354). Hence, the increased TGF-β in TME and TIME suppresses antitumor T cell immune response through metabolic reprogramming. The details of PD-1 signaling mediated T cell immunometabolic reprogramming responsible for T cell immunosuppression are discussed elsewhere (141). Blocking PD-1/PDL-1 signaling restores glucose in TME, which permits T cell glycolysis and IFN-γ production as an antitumor immune response (78). However, blocking PD-L1 directly in tumors inhibits their glycolysis via suppressing mTOR signaling and glycolysis enzymes (78). Tumor and immune cell-secreted and expressed molecules create a T cell-mediated immunosuppressive TIME in the TME to support tumor growth, proliferation, and metastasis via immunometabolic reprogramming.

Murine cancer models have indicated the role of B cells in tumor pathogenesis and immunity, including their regulatory role in innate immune cell infiltration in the premalignant tissue to promote chronic inflammation, which promotes epithelial carcinogenesis ( Figure 9 ) (355, 356). For example, antibodies released from activated B cells in premalignant tissues fuel chronic inflammation through Fcγ receptor (FcγR)-dependent innate immune cell infiltration into the preneoplastic and neoplastic TME ( Figure 9 ). Hence, B cells have been shown to promote cancer through promoting early malignancy via supporting chronic inflammation. However, in established tumors, B cells act as antitumor immune cells by promoting IFN-γ secreting Th1 immune cells, which are crucial for generating an adequate antitumor immunity in response to checkpoint inhibitors (357, 358). Even, intratumoral immunotherapy success depends on B and T cell collaboration (359, 360). In humans, intratumoral B cells are good prognosis markers for different cancers (361). However, the clonal diversity among infiltrated B cells affects survival of patients with cancer depending on type (362–364). For example, in TME or TIME, intratumoral B cell number highly depends on tertiary lymphoid structures (TLSs), as tumors without TLS have low B cell numbers (365, 366). Furthermore, B cell maturation, selection, and expansion occur in the mature TLS of tumor tissue that determines their antitumor (367, 368).

The mature TLS B cells increase antitumor T-cell activity in TIME and the responsiveness of tumors to immunotherapies ( Figure 9 ) (368). On the other hand, B cells in immature TLSs do not have potent antitumor action. Instead, they become tumor-supportive ( Figure 9 ). The B cell numbers, including the presence of switched memory B cells in tumor TLSs, guide the success of potential tumor immunotherapy and the associated patient survival (365). The details of B cells in TME and TIME are discussed elsewhere (361, 369–371). However, TLS maturation depends on the availability of extracellular ATP molecules (including the microbe-derived ones), which use ILC3-driven (IL-22, TNF-α, IL-8 and IL-2) and colony-stimulating factor 2 (CSF2)-dependent axis to induce the monocyte to macrophage transition in TIME (372, 373). These NCR⁺ILC3s are in higher numbers in the early stages (stage 1 or 2) than in later tumor stages, and their presence directly correlates with the density of TLSs in TIME (373). For example, gut microbiota may influence the efficacy of tumor immunotherapy via many immunomodulatory mechanisms, including the secretion of metabolites supporting the development and maturation of TLSs in TIME (374). Hence, a nutrient-competitive TME does not support the maturation of TLSs in TIME to escape from B cells and other immune cell-based antitumor immunity ( Figure 9 ).

B cells are divided into B1 B cells, conventional B2 cells, and marginal zone B (MZB) cells. MZB cells have an innate-like function and are present mainly in the spleen along with LNs and blood to take care of blood-borne pathogens and circulating antigens or foreign particles (375, 376). Out of B1 (form in fetal life and then depend on self-renewal in adult life) and B2 B cells (constantly keep developing in BM), B1 B cells are more dependent on OXPHOS and glycolysis and are more active at the resting stage than B2 B cells (377–379). In addition, B1 B cells acquire external lipids as lipid droplets. Furthermore, B1 B cells have a unique immunometabolic programming that depends on their location and specific functional properties as autophagy-deficient B1-a B cells down-regulate critical metabolic genes and accumulate dysfunctional mitochondria (379). Hence, the autophagy gene Atg7 is crucial to maintain their immunometabolic status to support their high proliferative and secretary functions.

Non-proliferative naïve B cells depend on OXPHOS due to the glycogen synthase kinase 3 (GSK3) activity required to maintain their metabolic quiescence and prevent proliferation (380). However, tumors have insufficient naive non-proliferating B cells (371). The germinal center (GC) B cells have different immunometabolic requirements depending on their location in the light zone (LZ) and dark zone (DZ). For example, in mature GCs (the microanatomical sites of antibody diversification (B cell clonal expansion) and affinity maturation), the DZ has large and mitotically active proliferating B cells (centroblasts) undergoing somatic hypermutation (SHM). These DZ B cells depend on glycolysis for the energy demand and differentiate into LZ B cells (381). Whereas the LZ of the GC contains a large portion of infiltrating and non-proliferative quiescent naïve B cells, which are also called centrocytes and compete for antigen presentation to follicular helper T (T_fh) cells mainly depend on OXPHOS (382, 383). However, LZ B cells expressing BCR and CD40 are rewired to highly express c-Myc, stimulating mitochondrial biosynthesis and genes required for glycolysis, promoting their re-entry to the DZ of the GC (384–386). These c-Myc-expressing centrocytes also express HIF-1α to support anaerobic glycolysis (387).

Memory B cells depend on OXPHOS for their metabolic demand. In contrast, plasma cells (PCs) or antibody-secreting B cells depend on OXPHOS and other carbon-utilizing metabolic pathways, including the TCA cycle, and nucleotide biosynthesis (PPS or PPP) that supports ribosome synthesis or ribogenesis, but not glycolysis (388–390). This glucose deprivation of PCs does not affect their humoral functions, but OXPHOS and glutaminolysis inhibition impairs their growth and differentiation. Hence, B cell activation requires considerable mitochondrial remodeling due to extensive OXPHOS. In addition, long-lived plasma cells (LLPCs) also depend on amino acid metabolism (glutaminolysis) and autophagosome formation (391, 392). Notably, PC metabolic reprogramming may also be affected by other factors, including the type of antibody production, location, and other metabolites (vitamins). For example, vitamin B1 supports the TCA cycle in Peyer’s patches in IgM-producing PCs without affecting IgA production (393). The tumor-infiltrating IgM memory B cells and switched memory B cells (IgG- and IgA-producing PCs) are present in different cancers, including breast cancer (BC), renal cell carcinoma (RCC), and head and neck squamous cell carcinoma (HNSCC) (394–396). The GC B cells, plasmablasts, and plasma cells are present in non-small cell lung cancers (NSCLCs), RCCs, HNSCC, and ovarian and prostate cancers (367, 395–397).

In TME or TIME infiltrated B cells under the influence of IL-6, IL-1β, IL-12p35, and low oxygen (tumor-promoting molecules), which polarize to regulatory B cells (B_regs), producing TGF-β, granzyme B (GZMB), IL-10, and IL-35, which promote tumor growth and metastasis (398–402). The metabolic reprogramming among B_regs in TIME is unclear, but IL-10 secretion depends on glucose influx-dependent OXPHOS, PPP, amino acid metabolism, and oxygen level in the TME. Also, a balance between B_regs and PCs derives potential antitumor immunity during pancreatic cancer (403). However, IL-35 in TME breaks this balance and stimulates the STAT3-paried box 5 protein (PAX5, a transcription factor crucial for B cell differentiation) complex, upregulating B cell lymphoma 6 (BCL6, a transcriptional regulator) in naive B cells. BCL6 inhibition in tumor-educated B cells reverses dysregulated B cell differentiation and stimulates the intra-tumoral accumulation of PCs and T_effs. This renders pancreatic tumors sensitive to anti-PD-1 blockade (403). Hence, B cell metabolic reprogramming in the TME or TIME alters their antitumor action and promotes their polarization to tumor-supportive B_regs.