Core Viewpoint - The study identifies AKR1B1 as a key regulatory enzyme in metabolic reprogramming and a potential biomarker and therapeutic target for hepatocellular carcinoma (HCC), suggesting that targeting AKR1B1 can reverse systemic therapy resistance in HCC [3][7]. Group 1: Research Findings - HCC is a major subtype of liver cancer and a leading cause of cancer-related deaths globally, with high incidence and mortality rates [2]. - The research team established HCC cell lines with multidrug resistance characteristics, observing enhanced metabolic activity in these cells [5]. - Multi-omics analysis revealed that glucose-lipid and glutathione metabolic pathways are overactive, playing critical roles in supporting tumor cell proliferation and survival [5]. Group 2: Mechanism of Resistance - The study constructed a metabolic reprogramming map for resistant HCC cells, identifying AKR1B1 as a key regulatory factor that maintains resistance by modulating energy metabolism and enhancing stress tolerance [5]. - The expression level of AKR1B1 is closely related to drug resistance and poor prognosis in HCC patients, highlighting its predictive value [5]. Group 3: Therapeutic Implications - The combination of Epalrestat, a clinically approved AKR1B1 inhibitor, with standard therapy (Lenvatinib) significantly alleviated resistance in HCC [7]. - The findings provide new insights into the mechanisms of resistance in HCC and lay the theoretical foundation for developing new predictive biomarkers and therapeutic strategies to overcome resistance [7].

Core Viewpoint - The study reveals that RIOK1 phase separation restricts PTEN translation via stress granules, promoting tumor growth in hepatocellular carcinoma (HCC) [2][3][6]. Group 1: Research Findings - RIOK1 is highly expressed in HCC and is associated with poor prognosis, activated by NRF2 under various stress conditions [6]. - RIOK1 facilitates liquid-liquid phase separation (LLPS) by incorporating IGF2BP1 and G3BP1 into stress granules, which sequester PTEN mRNA, reducing its translation [6]. - This process activates the pentose phosphate pathway, helping cells cope with stress and protecting them from the effects of tyrosine kinase inhibitors (TKIs) [6]. Group 2: Implications for Treatment - The small molecule Chidamide, a selective histone deacetylase inhibitor, can downregulate RIOK1 and enhance the efficacy of TKIs [6]. - RIOK1-positive stress granules were found in tumors of HCC patients resistant to Donafenib, indicating a potential target for overcoming drug resistance [6][7]. Group 3: Broader Context - The findings connect the dynamic changes of stress granules and metabolic reprogramming to the progression of HCC, suggesting potential strategies to improve TKI efficacy [7]. - A related article in Nature Cancer discusses how cancer cells form stress granules to adapt to stress and survive, highlighting the role of RIOK1-mediated phase separation in drug resistance [8].

Core Viewpoint - The study highlights the role of metabolic reprogramming in promoting immune suppression in hepatocellular carcinoma (HCC), which is crucial for developing targeted and effective anti-tumor strategies [2][3]. Group 1: Research Findings - The research integrates multi-omics data, including metabolomics, transcriptomics, and single-cell sequencing, to elucidate how tumor cells produce and actively export N1-acetylspermidine (N1-Ac-Spd), leading to immune suppression [3][4]. - N1-Ac-Spd accumulates in HCC tissues and increases in paired plasma compared to non-tumor liver tissues, promoting tumor progression and weakening the efficacy of immune checkpoint blockade (ICB) therapy in preclinical models [4][6]. - Inflammatory macrophages enhance the expression of SAT1 in HCC cells, which increases the export of N1-Ac-Spd through the polyamine transporter SLC3A2, creating an immunosuppressive tumor microenvironment [5][6]. Group 2: Mechanistic Insights - N1-Ac-Spd activates SRC signaling in a charge-dependent manner, leading to the polarization of CCL1+ macrophages and recruitment of regulatory T cells, which diminishes the effectiveness of ICB therapy [5][6]. - Blocking the synthesis of N1-Ac-Spd or targeting SLC3A2, SAT1, or CCL1 can significantly enhance the anti-tumor effects of ICB therapy [5][6]. Group 3: Implications for Treatment - The findings reveal mechanisms by which metabolic reprogramming fosters an immunosuppressive tumor microenvironment, providing theoretical foundations and potential intervention targets for enhancing HCC treatment [6][9].

Core Viewpoint - CAR-T cell therapy has shown remarkable efficacy in treating hematological cancers, but its effectiveness in solid tumors remains limited due to the challenging tumor microenvironment (TME) [1][2] Group 1: Research Findings - The study reveals that Foxp3 enhances the long-term efficacy of CAR-T cells through metabolic reprogramming, providing a survival advantage in solid tumor environments [2][7] - CAR-T Foxp3 cells exhibit a distinct metabolic reprogramming profile compared to conventional CAR-T cells, characterized by decreased aerobic glycolysis and oxidative phosphorylation, alongside increased lipid metabolism [5][9] - The interaction between Foxp3 and Drp1 drives the metabolic transition in CAR-T Foxp3 cells, which do not acquire the immunosuppressive functions typical of Treg cells [5][9] Group 2: Implications for Cancer Treatment - The findings establish a new strategy based on metabolic reprogramming to enhance CAR-T cell adaptability in harsh tumor microenvironments while maintaining therapeutic efficacy [9] - CAR-T Foxp3 cells demonstrate lower levels of exhaustion markers and exhibit stronger anti-tumor efficacy compared to traditional CAR-T cells [9][6]