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

The gap

Consensus across the literature

Supporting evidence — 3 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
• 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