Renal Cell Carcinomas (RCCs) are metabolically heterogeneous tumors with distinct genetic, epigenetic, and metabolic alterations. In clear cell Renal Cell Carcinoma, VHL gene loss leads to stabilization of Hypoxia Inducible Factors (HIF1α and HIF2α), promoting angiogenesis and metabolic reprogramming enhancing cellular energy production. Papillary Renal Cell Carcinoma, frequently harboring mutations in Tricarboxylic Acid cycle enzymes (FH, SDH), results in the accumulation of different “oncometabolites”, capable to drive pseudohypoxia and epigenetic dysregulation. Chromophobe Renal Cell Carcinoma is instead associated with mitochondrial defects and limited glycolytic activity. In this context, a tight interplay exists between metabolism and the epigenetic landscape. Oncometabolites are able to inhibit key chromatin-modifying enzymes, altering gene expression and promoting tumorigenesis. RCCs also exhibits frequent mutations in epigenetic regulators, further contributing to metabolic rewiring and tumor progression. Inhibiting oncometabolite accumulation, disrupting amino acid metabolism, modulating lipid anabolic routes, or targeting epigenetic enzymes could complement current treatments. Understanding the metabolic dependencies of RCC cells may lead to the development of novel, personalized therapies.
Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype with limited targeted therapeutic options, leading to higher mortality rates compared to other breast cancer subtypes. In our previous study, we identified that N-acyl sphingosine amidohydrolase 1 (ASAH1) is overexpressed in TNBC cells, and its genetic and pharmacological targeting suppresses TNBC growth and progression. In the current study, we performed a small-molecule screen using epigenetic inhibitors in combination with the ASAH1 inhibitor carmofur to identify potential epigenetic regulators that can be co-targeted to enhance the antitumor effect of carmofur. We identified the bromodomain containing protein 1 (BRD1) inhibitors (BAY-299, NI57 and OF1), which when combined with carmofur led to stronger inhibition of TNBC tumor growth in cell culture and in in vivo model compared to either single agent alone. Mechanistically, BAY-299 in combination with carmofur induced higher expression of the transcriptional repressor B-cell lymphoma 6 (BCL6), resulting in stronger inhibition of the anti-apoptotic gene, B-cell lymphoma 2 (BCL2) than either treatment alone. This consequently led to enhanced apoptosis in TNBC cells treated with both BAY-299 and carmofur. Collectively, these results identify a previously undocumented therapeutic combination of BRD1 inhibitors and ASAH1 inhibitor carmofur as a promising treatment strategy for TNBC.
Breast cancer recurrence remains a major cause of patient mortality. Recurrence arises from disseminated cancer cells that persist in a dormant state and can remain quiescent for extended periods before re-entering proliferation. Despite the clinical importance of this phenomenon, the cellular and molecular mechanisms that govern the awakening of dormant cancer cells remain incompletely understood. Inflammation has been extensively implicated in cancer progression; however, whether and how macrophages contribute to the awakening of dormant breast cancer cells is unclear. Using three-dimensional coculture systems, we show that macrophages promote the awakening of dormant breast cancer cells by remodeling the extracellular matrix (ECM), in vitro. We identify macrophage-derived matrix metalloproteinase-9 (MMP9) and lysyl oxidase (LOX) as key mediators of ECM remodeling, which in turn induces dormant cancer cell awakening. Mechanistically, macrophage-dependent ECM modifications trigger ligand-independent activation of EGFR/HER2 signaling in dormant cancer cells. Together, these findings establish a direct link between inflammation, ECM remodeling, and dormant cell awakening, revealing a previously unrecognized macrophage-cancer cell crosstalk that contributes to breast cancer recurrence.
Colorectal cancer (CRC) is frequently accompanied by dysregulation of lipid metabolism. However, how sphingolipid metabolism–associated regulators influence key cellular processes in CRC remains unclear. By integrating TCGA and GEO datasets with differential expression analysis and machine learning, we identified SMPD3 as a candidate regulator of CRC progression and antitumor immunity. SMPD3 was downregulated in CRC tissues, whereas higher SMPD3 expression was associated with earlier-stage disease and improved survival. Single-cell transcriptomic analysis and immunohistochemistry further showed that high SMPD3 expression was associated with increased intratumoral CD8⁺ T-cell infiltration. In immunocompetent syngeneic mouse models, Smpd3 overexpression suppressed tumor growth and increased intratumoral CD8⁺ T-cell accumulation, and this antitumor effect depended on an immunocompetent host environment. SMPD3-high CRCs also exhibited higher PD-1-related immunophenoscores and a more favorable response pattern in a retrospective cohort receiving anti-PD-1-based therapy. Consistently, Smpd3 overexpression combined with anti-PD-1 treatment produced the lowest tumor burden in syngeneic CRC models. Mechanistically, SMPD3 enhanced cell-surface MHC-I presentation without substantially altering total MHC-I protein abundance. B2m knockdown reduced MHC-I surface expression and attenuated SMPD3-associated CD8⁺ T-cell-mediated cytotoxicity and tumor suppression, supporting the functional involvement of the B2m/MHC-I antigen-presentation axis. Brefeldin A blockade and washout assays further implicated intracellular trafficking in SMPD3-mediated MHC-I surface presentation, and SMPD3 may exert its antitumor immune effects through an intracellular mode of action. Together, these findings identify SMPD3 as a tumor-intrinsic regulator linking MHC-I surface presentation to CD8⁺ T-cell antitumor immunity and support its further evaluation as a candidate biomarker for PD-1 blockade responsiveness in CRC.
The 6th International Meeting “Metabolism and Cancer” was held at the Convention Center in La Grande Motte, France, on October 8–10, 2025. The three-day conference brought together 240 participants from eleven countries and featured 29 scientific presentations, including 15 invited lectures delivered by leading investigators in the field of oncometabolism. The program was structured into four thematic sessions: (i) diet, cachexia, microbiome, and microenvironment; (ii) stem cells and metabolic plasticity; (iii) epigenetics, epitranscriptomics, and metabolism; and (iv) metabolic control of drug resistance, therapy, and biomarkers. This meeting report highlights key conceptual advances and emerging directions discussed during the conference. Future progress in cancer metabolism will depend on elucidating the cross-talk between tumors and peripheral tissues, as organism-level metabolic regulation is likely to critically influence tumor growth, plasticity, and treatment sensitivity. Moving forward, a systems-level integration of metabolic, genomic, and spatial data is poised to redefine cancer metabolism from a descriptive field into a source of actionable vulnerabilities for precision oncology.
