Weiling He

The hepatic microenvironment undergoes dynamic remodelling in advanced liver fibrosis. Hyaluronic acid (HA), a key component of this fibrotic microenvironment, plays a key role in disease progression. While cellular senescence is one of the fates that activated HSCs undergo and is associated with fibrosis resolution, the relationship between HA and HSC senescence in advanced liver fibrosis remains unclear. This study aimed to elucidate the specific mechanisms by which HA regulates HSC senescence. Here, intrahepatic HSC transplantation confirmed that an advanced fibrotic microenvironment inhibited HSC senescence and led to its sustained activation. Mechanistically, low-molecular-weight (LMW) HA promotes HSC activation via the CD44-p38-ATF2 axis, while HMW-HA simultaneously inhibits HSC senescence through the TLR4-SerpinE1 axis. Furthermore, HA synthesis is mediated by MASP1. MASP1 enhances the m6A methylation of HAS2 via METTL3, leading to increased HAS2 mRNA levels and consequently elevated HMW-HA synthesis, and HYAL2 mediates the conversion of HMW‑HA to LMW‑HA. Targeted knockdown of MASP1 in the liver reversed HA metabolism, subsequently promoting HSC senescence and alleviating liver fibrosis. Therefore, targeting HA metabolism to induce HSC senescence for activated HSC removal may represent a novel therapeutic strategy for liver fibrosis.

The macrotrabecular-massive (MTM) subtype of hepatocellular carcinoma (HCC) is associated with aggressive biology and poor prognosis. We aimed to develop a CT-based artificial intelligence model (DeepCT-MTM) for the noninvasive prediction of MTM-HCC and investigate its prognostic utilities as well as biological underpinnings. A total of 3118 patients with HCC were included from 20 tertiary-care hospitals. DeepCT-MTM was developed and validated among 832 patients with early-stage HCC undergoing resection (the resection set) and extrapolated to 2286 patients (including 480 prospectively-collected ones) with intermediate/advanced-stage HCC receiving IATs. DeepCT-MTM’s predictive performance for MTM-HCC was evaluated using the area under the receiver operating characteristic curve (AUC), and its prognostic values were investigated for progression-free survival (PFS) and overall survival (OS). In the external test cohort of the resection set, DeepCT-MTM predicted MTM-HCC with an AUC of 0.845. The DeepCT-MTM-predicted high-risk group had worse PFS and OS across all IAT sets (all P < 0.05).. DeepCT-MTM is effective for noninvasively predicting MTM-HCC and may help selecting patients who benefit from a combination of IAT with immunotherapy and anti-angiogenic therapy. However, prospective validations are warranted for these hypothesis-generating findings.

The development of nanoanticancer agents has garnered significant interest, particularly for their application in the second near-infrared (NIR-II) phototherapy. Despite the promise that nanoparticles hold for tumor phototherapy, their limited light absorption efficiency and tumor accumulation ability substantially constrain their effectiveness in practical applications. This necessitates not only a profound comprehension of nanoparticle properties but also an intricate understanding of their targeting/delivery mechanisms. In this study, we showcase the impressive outcomes achieved by combining small molecular photothermal agents (PTAs) with cationic polymer (PWS5@NPs). By harnessing the exceptional NIR-II photothermal properties of aza-boron-dipyrromethene (aza-BODIPY) derivatives and the protonation/deprotonation characteristics of N,N-dimethyl acrylamide (PA1), we have successfully engineered multifunctional nanoparticles that facilitate efficient in situ enrichment of osteosarcoma via active endocytosis. Furthermore, molecular self-assembly reduces the size of the nanoparticles and diminishes the interactions between aza-BODIPY molecules within the polymer matrix, markedly improving the light absorption efficiency of the nanoparticles. This cationic polymer-photothermal agent conjugate design not only amplifies the fluorescence brightness of the nanoparticles but also enhances the photothermal therapy (PTT) efficacy against in situ osteosarcoma.

The efficacy of immunotherapy in colorectal cancer (CRC) is frequently limited by an immunosuppressive tumor microenvironment. Here, we identify exonuclease/endonuclease/phosphatase domain‐containing protein 1 (EEPD1), a gatekeeper of homologous recombination (HR) repair, as a key driver of this immune exclusion. Downregulation of EEPD1 profoundly compromises HR in CRC cells, which curtails their proliferative and metastatic capacities in vitro and in vivo. Mechanistically, EEPD1 deficiency fuels genomic instability, leading to cytosolic DNA accumulation and activation of the cGAS‐STING‐type I interferon axis. This cascade promotes dendritic cell maturation, skews macrophages toward a proinflammatory M1 phenotype, and enhances tumor‐associated antigen presentation, culminating in robust CD8 ⁺ T cell activation and cytotoxicity. Our findings elucidate a direct mechanism by which targeting EEPD1 sensitizes CRC to anti‐PD1 immunotherapy. Our work establishes EEPD1 as a promising therapeutic target to overcome immune checkpoint blockade resistance in colorectal cancer.