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Open research questions in Cancer, Lipids, and Metabolism

27 unresolved questions extracted from the limitations and future-work sections of 142 Cancer, Lipids, and Metabolism papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • Metabolic adaptations—including enhanced lipid catabolism, oxidative phosphorylation (OXPHOS), and autophagy—are major drivers of chemoresistance; however, the molecular mechanisms underpinning this metabolic reprogramming remain poorly understood.

    Carboxylesterase 1 is a core metabolic vulnerability of platinum-resistant high-grade serous ovarian carcinoma · 2026 · DOI

  • Carboxylesterase 1 (CES1), an NF-κB-regulated neutral lipase, supports malignant cell survival under nutrient-depleted conditions in other cancers, but its role in HGSOC has not been explored.

    Carboxylesterase 1 is a core metabolic vulnerability of platinum-resistant high-grade serous ovarian carcinoma · 2026 · DOI

  • Because invasion was unchanged and no proliferative, apoptotic, or other functional endpoint was assessed, the biological significance of these phosphorylation changes for cell behavior remains to be determined. As this study examined short-term signaling responses, functional consequences such as proliferation, apoptosis, or migra- tion remain to be determined in future studies.

    Sweet apple e-cigarette vapor differentially modulates the mTOR pathway in oral squamous cell carcinoma cell lines · 2026 · DOI

  • Deregulation of sphingolipid (SL) metabolism is well-established across many cancers, yet the underlying mechanisms that drive changes in SLs are poorly understood.

    Oncogene-driven metabolic regulation of Dihydroceramide Desaturase 1 (DES1) converges on GAPDH in matrix-detached conditions · 2026 · DOI

  • Furthermore, while MC-derived lipid mediators such as prostaglandins and leukotrienes facilitate angiogenesis and immune evasion (Lichterman and Reddy, 2021; Oldford and Marshall, 2015), their temporal production kinetics under hypoxia or nutrient restriction remain poorly defined (Gao et al. However, the clinical feasibility of incorporating metabolic immunotherapy combinations in ESCC cohorts remains uncertain, particularly regarding whether systemic MC depletion might compromise host pathogen defense (Qu et al.

    Mast cell driven immunometabolism as a therapeutic entry point in ESCC · 2026 · DOI

  • ABSTRACT Fatty acids (FAs) create a pro‐metastatic niche in multiple cancers, but how the tumor microenvironment (TME) counteracts FA stress remains unclear.

    CEBPG‐Mediated Palmitic Acid Adaptation of Cancer‐Associated Fibroblasts Drives Metastasis of Oral Squamous Cell Carcinoma · 2026 · DOI

  • Early-stage lung adenocarcinoma (LUAD) in never smokers exhibits distinct biological features, yet the metabolic programs driving early invasion remain unclear.

    Proteomic and lipidomic analyses reveal molecular subtypes and potential targets in early-stage lung adenocarcinoma among non-smokers · 2026 · DOI

  • Background High-density lipoprotein (HDL) cholesterol exerts anti-inflammatory, antioxidative, and endothelial-protective effects, yet its role in interstitial lung abnormalities (ILA) remains unclear.

    Associations between High-Density Lipoprotein Cholesterol and Interstitial Lung Abnormalities in the Korean National Lung Cancer Screening · 2026 · DOI

  • Over the past few decades, extensive research has delin- eated links between tumorigenesis and metabolic dys- regulation. However, relatively few metabolism-targeted anti-cancer agents have delivered durable and broadly applicable clinical benefit. This may reflect two issues: marked tumor heterogeneity and a long-standing focus on cancer cell–intrinsic programs rather than tumor- extrinsic components. Non-malignant immune cells can substantially influence tumor progression, metastasis, and therapeutic response; therefore, cholesterol-targeted strategies should explicitly account for these compart- ments. Recent advances in the crosstalk between choles- terol metabolism and oncogenic and immune signaling underscore the need for deeper investigation of choles- terol metabolic remodeling not only in cancer cells but also across the tumor microenvironment throughout ini- tiation, progression, metastasis, and treatment response. Despite meaningful progress, critical gaps remain that impede comprehensive understanding and translation. Key outstanding questions include: (1) Which nodes in cholesterol biosynthesis, uptake, trafficking, efflux, or esterification can be targeted to achieve precise tumor control while sparing normal tissues? (2) How does cho- lesterol homeostasis change in normal tissues during carcinogenesis, and what intrinsic and extrinsic driv- ers govern these shifts? (3) Do primary tumors and their metastatic lesions of the same origin exhibit distinct cho- lesterol-metabolic programs and therapeutic vulnerabili- ties? (4) Which signaling pathways differentially regulate cholesterol metabolism in cancer versus immune cells, Ma et al. Molecular Cancer (2026) 25:115 and how do these interactions shape antitumor immu- nity and responses to immunotherapy? Addressing these issues will require mechanistically grounded, context- specific, and cell-type-resolved analyses of cholesterol metabolism in tumors and the tumor microenvironment, ideally integrating spatial profiling with functional per- turbation. Collectively, deeper insight into tumor-associ- ated cholesterol remodeling will guide the development of biomarker-driven, cholesterol-targeted strategies with improved efficacy and reduced toxicity, including rational combination regimens supported by emerging clinical evidence. Authors’ contributions Q.M. conceived and led the review; designed the analytical framework, conducted evidence synthesis and visualization, and wrote the original draft. B.N.C. and T.T.L. contributed to the literature search and writing—review & editing. X.G.L. and Y.H.L. supervised the study and revised the manuscript. All authors approved the final version.

    Targeting cholesterol-driven immunometabolism in cancer: from molecular circuits to clinical translation · 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 immunosuppressive 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 metabolismreveal 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 contextdependent 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. To overcome these bottlenecks, cell-specific and precise immunometabolic rewiring has emerged as a promising therapeutic 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. Similarly, genetically engineering FOXP3 into CAR-T cells optimizes their intrinsic lipid utilization, conferring superior persistence and therapeutic efficacy. 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 and pinpoints cholesterol accumulation in specific myeloid populations as a key immunosuppressive mechanism. Proteomics extends this functional mapping by systematically profiling differential protein expression and identifying key metabolic regulators in both immune and tumor cells. 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.

    Lipid metabolism reprogramming shapes the immune landscape in the tumor microenvironment · 2026 · DOI

  • Furthermore, the integration of multi-omics data revealed the activation of compensatory mechanisms aimed at restoring cellular homeostasis, including metabolic rewiring and stress-response pathways, although these responses were insufficient to counteract nanosystem-induced cytotoxicity.

    Systems-Level Multi-Omics Analysis Resolves the Mechanism of Action of a Novel Multifunctional Nanosystem Against Triple-Negative Breast Cancer · 2026 · DOI

  • However, its mechanisms in metabolic dysfunction-associated fatty liver disease (MAFLD) progression remain to be identified.

    Activated cGAS-STING signaling promotes malignancy in metabolic dysfunction-associated fatty liver disease <i>via</i> mitochondrial DNA and immune cell dysfunction · 2026 · DOI

  • While metabolic dysregulation is a hallmark of hepatocellular carcinoma (HCC), how nutrient overload impairs antitumor immunity remains unclear.

    A Paracrine Dietary Lipid Axis Constrains Antitumor Immunity in Liver Cancer · 2026 · DOI

  • Cancer is intricately linked to metabolic disorders, yet a comprehensive atlas delineating the impact of endocrine, nutritional and metabolic diseases (ENMs) on cancer trajectories remains unexplored.

    Endocrine, nutritional and metabolic diseases drive cancer risk through subtype-specific and shared proteomic mediators · 2026 · DOI

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27 open questions have been extracted from the limitations and future-work passages of 142 Cancer, Lipids, and Metabolism papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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