The next phase of cancer immunometabolism research will require greater spatial, temporal, and cellular resolution. Tumors are metabolically heterogeneous ecosystems, and nutrient gradients vary acros

The gap

Consensus across the literature

Supporting evidence — 5 representative gaps

• Lipid metabolism reprogramming shapes the immune landscape in the tumor microenvironment (2026) · doi

  Lipid metabolism reprogramming is a central driver of the immune landscape within the TME. Beyond directly conferring proliferative and survival advantages to tumor cells, this metabolic rewiring orchestrates widespread immune evasion. Specifically, aberrant lipid metabolism induces severe metabolic dysfunction and exhaustion in antitumor effector cells, notably CD8+ T cells and NK cells, while simultaneously activating and fueling immunosup- pressive populations, such as TAMs. Beyond these cell-intrinsic alterations, lipid-mediated intercellular crosstalk synergistically perpetuates this hostile niche. Thus, dysregulated lipid metabolism fundamentally underpins tumor escape from immune surveillance and represents a key mechanism of immunotherapy resistance. Current pharmacological agents targeting lipid metabolismre- veal that blocking tumor–immune crosstalk and disrupting TAM lipid metabolism represent primary strategies to remodel the immunosuppressive microenvironment. Despite this potential, the clinical application of systemic metabolic interventions is often hindered by the profound heterogeneity of the TME and detrimental off-target effects. This is exemplified by the context- dependent effect of statins, which may inadvertently exacerbate cholesterol starvation in CD8+ T cells, leading to profound suppression of their activation and survival [73, 113]. Furthermore, statins can induce unexpected metabolic rewiring, such as by driving SREBP1/TGFβ signaling in KRAS-mutant pancreatic cancer models, thereby significantly enhancing tumor aggressiveness [172]. To overcome these bottlenecks, cell-specific and precise immunometabolic rewiring has emerged as a promising ther- apeutic strategy. For example, CD40 agonism reprograms TAMs via FAO- and ACLY-mediated epigenetic rewiring, enabling robust M1-like polarization even in a glucose-deprived TME [173]. Similarly, genetically engineering FOXP3 into CAR-T cells optimizes their intrinsic lipid utilization, conferring superior persistence and therapeutic efficacy [174]. The omics era has fundamentally transformed lipid metabolism research from descriptive observation to mechanistic discovery through the integration of multilayered technologies. Multiomics strategies now couple transcriptomics with metabolomics or lipidomics to directly correlate gene expression with metabolic flux. This integrated approach links transcriptional changes to functional metabolite loss [75] and pinpoints cholesterol accumu- lation in specific myeloid populations [158] as a key immunosup- pressive mechanism. Proteomics extends this functional mapping by systematically profiling differential protein expression and identifying key metabolic regulators in both immune [99] and tumor cells [74]. Furthermore, by characterizing the protein cargo Cellular & Molecular Immunology 9 y t i l i b i t a p m o c o t s i h r o j a m ] 2 5 1 [ ] 4 5 1 [ ] 6 3 1 [ ] 5 4 1 [ ] 9 8 [ ] 1 7 1 [ ] 0 7 1 [ ] 6 2 1 [ ] 3 6 [ Y.-W. Du

  Keywords: lipid cells metabolic metabolism immune tumor rewiring speci beyond directly conferring survival immunosup pressive populations
• Metabolic adaptations of immunosuppressive cells in cancer: mechanisms and therapeutic targets (2026) · doi

  Immunosuppressive cells within the TME—including Treg cells, MDSCs, TAMs and TANs—exhibit remarkable metabolic plasticity that enables them to thrive under nutrient-deprived, hypoxic and acidic conditions. By contrast, effector immune cells such as CD8⁺ T cells and NK cells are metabolically disadvantaged in this hostile environment, leading to impaired function and reduced antitumor efficacy. This metabolic antagonism is a critical barrier to the success of current immunotherapies. Recent studies have highlighted how these suppressive popula- tions exploit key metabolic pathways—such as FAO, glycolysis, amino acid catabolism and lactate utilization—to maintain their immunosuppressive phenotypes. Moreover, the TME is shaped by metabolic byproducts such as lactate, ROS and adenosine, which further inhibit effector cell function and reprogramming. These insights have opened new avenues for metabolic intervention to reprogram the immune landscape of tumors. Experimental & Molecular Medicine function. Second, Moving forward, several critical areas warrant further investi- gation. First, there is an urgent need to identify context-specific metabolic checkpoints that selectively impair suppressive cells without compromising effector cell the development of metabolic imaging tools and spatial metabo- lomics will be essential the dynamic interplay to decipher between immune cell subsets in vivo. Third, combinatorial integrating metabolic modulators with immune strategies checkpoint therapies should be inhibitors or adoptive cell systematically evaluated to overcome resistance mechanisms and enhance durable responses. Fourth, some compounds may have off-target effects, for example, although inhibition of long- chain FAO with etomoxir has been widely used to dissect the metabolic role of FAO in lymphocytes, Raud, O’Connor and colleagues demonstrated—using Cpt1a genetic ablation models —that the effects of etomoxir on T cell differentiation and function are independent of Cpt1a expression122,123. This finding highlights the potential for off-target effects of etomoxir on cellular metabolism, particularly when used at high concentra- tions. Finally, translating these findings into clinically actionable biomarkers and therapies will require a multidisciplinary approach encompassing immunology, oncology, systems biol- ogy and bioengineering. Ultimately, targeting the unique metabolic vulnerabilities of immunosuppressive cells represents a promising strategy to tip the immunological balance in favor of antitumor immunity and improve patient outcomes across a broad spectrum of cancers. REFERENCES 1. Swanton, C. et al. Embracing cancer complexity: hallmarks of systemic disease. Cell 187, 1589–1616 (2024). 10 J. Kim et al. 2. Lim, S. A. Metabolic reprogramming of the tumor microenvironment to enhance immunotherapy. BMB Rep. 57, 388–399 (2024). 33. Wan, Y. Y. Regulatory T cells: Immunol. 7, 204–210 (2010). immune suppression and beyond. Cell Mol. 3. Baghban, R. et al. Tumor microenvironment complexity and therapeutic impli- 34. Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by cations at a glance. Cell Commun Signal 18, 59 (2020). 4. Poyia, F., Neophytou, C. M., Christodoulou, M. I. & Papageorgis, P. The role of tumor microenvironment in pancreatic cancer immunotherapy: current status and future perspectives. Int. J. Mol. Sci. (2024). the transcription factor Foxp3. Science 299, 1057–1061 (2003). 35. Dikiy, S. et al. A distal Foxp3 enhancer enables interleukin-2 dependent thymic Immunity 54, lineage commitment for robust immune tolerance.

  Keywords: metabolic cell cells immune function immunosuppressive effector effects etomoxir tumor microenvironment enables antitumor critical current
• Macrophage metabolic reprogramming in sepsis-associated acute lung injury: mechanisms and therapeutic strategies (2026) · doi

  Macrophage polarization is intrinsically linked to metabolic reprogramming. Pro-inflammatory macrophages rely on enhanced glycolysis, which sustains the production of inflammatory media- tors such as TNF-a, IL-1b, and ROS. In contrast, anti-inflammatory macrophages predominantly utilize OXPHOS and fatty acid oxi- dation to support their reparative and immunoregulatory functions. These distinct metabolic programs not only meet the specific energetic demands of each phenotype but also actively shape macrophage effector responses, thereby influencing the trajectory and resolution of inflammatory processes during S-ALI (207, 208). As sepsis progresses, the metabolic landscape of macrophages undergoes dynamic temporal shifts: the early hyperinflammatory phase is characterized by enhanced glycolysis, while the late immunosuppressive phase exhibits impaired OXPHOS and FAO, with profound defects in the carnitine shuttle observed specifically in non-survivors (62, 160). This biphasic metabolic trajectory underscores the necessity of considering disease stage when design- ing therapeutic interventions. The traditional M1/M2 binary classification, while heuristically useful, warrants critical reflection. As discussed above, macrophage activation in vivo encompasses a fluid continuum of functional states shaped by the convergence of diverse signals, intracellular pathways, and epigenetic modifications (34–36). The binary model, despite its experimental convenience, fails to capture the interme- diate and hybrid phenotypes that are particularly prevalent in complex inflammatory environments such as the septic lung. A related and equally important consideration is the heterogeneity of macrophage populations within the lung (209). Alveolar macro- phages, interstitial macrophages, and recruited monocyte-derived macrophages possess distinct developmental origins, transcrip- tional programs, and homeostatic functions. However, the extent to which these subpopulations undergo divergent metabolic reprogramming during S-ALI remains poorly characterized. In the current literature, most mechanistic insights have been derived from reductionist models employing BMDMs, peritoneal macro- phages, or immortalized cell lines, and it remains unclear how faithfully these systems recapitulate the metabolic behavior of specific lung-resident subsets. Moreover, local microenvironmental factors, including oxygen tension, pH, nutrient availability, and extracellular matrix composition, are likely to exert profound influences on macrophage metabolism within different compart- ments of the injured lung, yet these variables are rarely considered in experimental designs. Future studies should therefore adopt multidimensional analytical approaches, including single-cell trans- criptomics, metabolomics, and spatial profiling, to more precisely define the macrophage activation landscape in S-ALI, to identify functionally discrete subsets that may serve as specific therapeutic t a r g e t s , a n d t o i n

  Keywords: macrophage metabolic ammatory macrophages speci lung reprogramming enhanced glycolysis oxphos functions distinct programs trajectory landscape
• The landscape of cellular immune alteration in systemic lupus erythematosus (2026) · doi

  The pathogenesis of SLE is driven by multifaceted dysregulation across both adaptive and innate immunity, with aberrant T and B cell activation playing a central role (Figure 6). Expansion of Th17 and Tfh subsets, coupled with impaired Treg function, promotes sustained inflammation and high-affinity autoantibody production, ultimately leading to immune complex deposition and tissue damage (59, 236). T cell metabolic abnormalities—such as elevated glycolysis and mitochondrial dysfunction—not only sustain path- ological activation but also provide actionable targets for metabolic intervention (e.g., mTOR inhibitors, glycolysis blockers) (41). Additionally, T and B cells form a pathogenic feedback loop via CD40–CD40L and IL-21 signaling, exacerbated by deficient Breg- mediated regulation, underscoring the need to restore immune tolerance (237). Innate immune dysregulation further amplifies disease. Persistent IFN-a production by pDCs via TLR7/9, M1- biased macrophage polarization, defective apoptotic clearance, and mitochondrial ROS accumulation collectively fuel chronic inflam- mation (11, 15). Excessive NETosis and LDG accumulation expose nuclear autoantigens, augmenting autoantibody responses and damaging endothelium, particularly in lupus nephritis (20). Impaired NK cytotoxicity and cytokine imbalance hinder clearance of autoreactive cells, destabilizing immune homeostasis (25). Emerging evidence has established gut microbiome dysbiosis as a key environmental factor contributing to immune dysregulation in SLE. Gut microbiome dysbiosis, characterized by depletion of butyrate-producing bacteria and enrichment of pro-inflammatory taxa such as Ruminococcus gnavus, further contributes to immune dysregulation through gut barrier dysfunction, molecular mimicry, and SCFA deficiency (200, 238). Current treatment of SLE follows a treat-to-target strategy, com- bining universal background therapy with hydroxychloroquine, judi- cious glucocorticoid use, and steroid-sparing immunosuppressants such as mycophenolate mofetil, azathioprine, and cyclophosphamide, selected according to disease severity and organ involvement (239). Among these, hydroxychloroquine remains foundational due to its ability to reduce disease activity, prevent flares, and provide long-term vascular protection (240). The growing understanding of SLE patho- genesis has guided the development of targeted biologics. Given the central role of B cell hyperactivity driven by BLyS overexpression, belimumab (anti-BLyS) has demonstrated efficacy in systemic disease

  Keywords: immune dysregulation disease cell driven innate activation central role impaired autoantibody production metabolic glycolysis mitochondrial
• Tumor–immune metabolic tug-of-war: from immune escape to targeting metabolic rewiring in cancer therapy (2026) · doi

  The next phase of cancer immunometabolism research will require greater spatial, temporal, and cellular resolution. Tumors are metabolically heterogeneous ecosystems, and nutrient gradients vary across regions, disease stages, and therapeutic contexts. spatial Integrating metabolomics, transcriptomics, single-cell profiling, and functional immune analyses will be essential to map how metabolic circuits evolve during progression and treatment. Therapeutically, the challenge is no longer simply to inhibit tumor metabolism but to recalibrate metabolic ecosystems. Because immune cells share many metabolic dependencies with tumor cells, indiscriminate metabolic blockade risks impairing anti-tumor immunity. Rational combination strategies (pairing tumor- directed metabolic inhibitors with ICB, co-stimulatory agonists, or adoptive cell therapies) offer a more nuanced approach. In parallel, therapeutic lymphocytes may enhance their resilience within nutrient- and oxygen-restricted environments. conditioning of vivo metabolic ex A deeper understanding of metabolic plasticity will also be crucial. Many suppressive immune populations thrive precisely because they exploit alternative fuel sources. Identifying context- specific metabolic vulnerabilities, rather than broadly targeting entire pathways, may allow selective disruption of tumor- promoting circuits while preserving or enhancing effector function. Ultimately, metabolic pathway rewiring should be viewed not merely as a hallmark of cancer but as a strategic battlefield. By learning how to manipulate the rules of metabolic engagement, future therapies may transform the tumor–immune tug-of-war into a coordinated and sustained anti-tumor response. Frontiers in Cell and Developmental Biology 29 frontiersin.org Foglia et al. 10.3389/fcell.2026.1823145

  Keywords: metabolic tumor immune cell cancer spatial ecosystems nutrient therapeutic circuits cells anti therapies next phase