Core Viewpoint - The study reveals that RIOK1 phase separation restricts PTEN translation via stress granules, promoting tumor growth in hepatocellular carcinoma (HCC) [4][12]. Group 1: Mechanism of Drug Resistance - RIOK1 phase separation mediates the formation of stress granules under TKI treatment stress, recruiting IGF2BP1 and G3BP1 to form dynamic stress granules [11]. - Stress granules selectively encapsulate PTEN mRNA, inhibiting its translation into PTEN protein, leading to the inactivation of the PTEN/PI3K/AKT pathway [11]. - The loss of PTEN activates the pentose phosphate pathway (PPP), increasing NADPH production and antioxidant capacity, helping cancer cells eliminate TKI-induced reactive oxygen species (ROS) [11]. Group 2: Key Findings and Clinical Relevance - The NRF2-RIOK1 regulatory axis is activated by oxidative stress (e.g., TKI treatment), upregulating RIOK1 expression and enhancing cancer cell adaptability through a positive feedback loop [11]. - The study establishes a causal chain linking stress granules, metabolic reprogramming, and TKI treatment resistance in HCC [12]. Group 3: Research Significance and Translational Directions - Targeting RIOK1 phase separation may disrupt the cancer cell's "stress buffering system," providing a new direction to improve TKI efficacy [12]. - Combination therapy of TKI and Chidamide may synergistically enhance anti-tumor effects [13]. - RIOK1 expression levels or the dynamics of stress granules could serve as predictive biomarkers for TKI efficacy, guiding personalized treatment [13].

Core Viewpoint - The study highlights the role of gut microbiota, specifically the metabolite urocanic acid (UCA), in enhancing the efficacy of cancer immunotherapy when combined with tyrosine kinase inhibitors (TKIs) [3][8][11]. Group 1: Research Findings - The research demonstrates that TKIs increase the abundance of the gut bacterium Muribaculum gordoncarteri and its metabolite UCA, which enhances the response to immune checkpoint blockade (ICB) therapy [8][9]. - UCA interacts with IκBα to inhibit NF-κB activation in endothelial cells, thereby reducing the recruitment of myeloid-derived suppressor cells (MDSCs) mediated by CXCL1 [9][11]. - Higher levels of UCA and Muribaculum gordoncarteri are found in the feces of patients who respond to ICB therapy compared to non-responders, suggesting their potential as predictive biomarkers for treatment response [8][9][11]. Group 2: Implications for Cancer Treatment - The findings indicate that the interaction between TKIs and gut microbiota could be a crucial factor in improving cancer treatment outcomes, particularly for patients who currently do not respond well to existing therapies [7][9]. - Understanding the mechanisms by which UCA enhances ICB therapy could lead to new strategies for increasing the effectiveness of cancer immunotherapy [3][11].

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].