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Abstract The constrained effectiveness of photodynamic therapy (PDT) has impeded its widespread use in clinical practice. Urgent efforts are needed to address the shortcomings faced in photodynamic therapy, such as photosensitizer toxicity, short half‐life, and limited action range of reactive oxygen species (ROS). In this study, a biodegradable copolymer nanoamplifier is reported that contains ruthenium complex (Ru‐complex) as photosensitizer (PS) and rhenium complex (Re‐complex) as carbon monoxide (CO)‐release molecule (CORM). The well‐designed nanoamplifier brings PS and CORM into close spatial proximity, significantly promotes the utilization of light‐stimulated reactive oxygen species (ROS), and cascaded amplifying CO release, thus enabling an enhanced synergistic effect of PDT and gas therapy for cancer treatment. Moreover, owing to its intrinsic photodegradable nature, the nanoamplifier exhibits good tumor accumulation and penetration ability, and excellent biocompatibility in vivo. These findings suggest that the biodegradable cascaded nanoamplifiers pave the way for a synergistic and clinically viable integration of photodynamic and gas therapy.

Abstract Introduction Regorafenib remains the standard and widely used second‐line strategy for advanced hepatocellular carcinoma (HCC). There is still a lack of large‐scale multicenter real‐world evidence concerning the concurrent use of regorafenib with immune checkpoint inhibitors (ICI). This study aims to evaluate whether combining regorafenib with ICI provides greater clinical benefit than regorafenib monotherapy as second‐line therapy for advanced HCC under real‐world circumstances. Patients and Methods The study included 208 patients from five medical facilities. One hundred forty‐three patients received regorafenib plus ICI combination therapy, while 65 patients received regorafenib monotherapy. Propensity score matching (PSM) analysis was employed. Results The regorafenib plus ICI group demonstrated significantly higher objective response rate (24.3% vs. 10.3%, after PSM, p = 0.030) and disease control rate (79.4% vs. 50.0%, after PSM, p

Abstract Background Hepatocellular carcinoma (HCC) cells undergo reprogramming of glucose metabolism to support uncontrolled proliferation, of which the intrinsic mechanism still merits further investigation. Although regulatory factor X6 (RFX6) is aberrantly expressed in different cancers, its precise role in cancer development remains ambiguous. Methods Microarrays of HCC tissues were employed to investigate the expression of RFX6 in tumour and adjacent non‐neoplastic tissues. Functional assays were employed to explore the role of RFX6 in HCC development. Chromatin immunoprecipitation, untargeted metabolome profiling and sequencing were performed to identify potential downstream genes and pathways regulated by RFX6. Metabolic assays were employed to investigate the effect of RFX6 on glycolysis in HCC cells. Bioinformatics databases were used to validate the above findings. Results HCC tissues exhibited elevated expression of RFX6. High RFX6 expression represented as an independent hazard factor correlated to poor prognosis in patients with HCC. RFX6 deficiency inhibited HCC development in vitro and in vivo, while its overexpression exerted opposite functions. Mechanistically, RFX6 bound to the promoter area of phosphoglycerate mutase 1 (PGAM1) and upregulated its expression. The increased PGAM1 protein levels enhanced glycolysis and further promoted the development of HCC. Conclusions RFX6 acted as a novel driver for HCC development by promoting aerobic glycolysis, disclosing the potential of the RFX6–PGAM1 axis for therapeutic targeting.

Abstract Transarterial chemoembolization (TACE) is the major treatment for advanced hepatocellular carcinoma (HCC), but it may cause hypoxic environment, leading to rapid progression after treatment. Here, using high‐throughput sequencing on different models, S100 calcium binding protein A9 (S100A9) is identified as a key oncogene involved in post‐TACE progression. Depletion or pharmacologic inhibition of S100A9 significantly dampens the growth and metastatic ability of HCC. Mechanistically, TACE induces S100A9 via hypoxia‐inducible factor 1α (HIF1A)‐mediated pathway. S100A9 acts as a scaffold recruiting ubiquitin specific peptidase 10 and phosphoglycerate mutase family member 5 (PGAM5) to form a tripolymer, causing the deubiquitination and stabilization of PGAM5, leading to mitochondrial fission and reactive oxygen species production, thereby promoting the growth and metastasis of HCC. Higher S100A9 level in HCC tissue or in serum predicts a worse outcome for HCC patients. Collectively, this study identifies S100A9 as a key driver for post‐TACE HCC progression. Targeting S100A9 may be a promising therapeutic strategy for HCC patients.