Crit Rev Oncol Hematol. 2026 Mar 27;222:105305. doi: 10.1016/j.critrevonc.2026.105305. Online ahead of print.

ABSTRACT

The management of hepatocellular carcinoma (HCC) faces substantial and evolving challenges, driven by its aggressive biology, drug resistance, and the clinical urgency to detect recurrence. The treatment paradigm has undergone a profound transformation, evolving from surgical interventions and molecular targeted agents to the current era dominated by immunotherapy. Immune checkpoint inhibitors, particularly when used in combination with anti-angiogenic drugs or as part of dual-checkpoint blockade regimens, have established a new first-line standard of treatment for advanced HCC, delivering unprecedented survival improvements. Despite this progress, significant obstacles remain, including primary and acquired resistance, variable patient responses, and notably reduced efficacy in specific etiological subgroups. This comprehensive review synthesizes the emerging modalities such as bispecific antibodies, adoptive cell therapies, and innovative rational combinations that integrate systemic immunotherapy with locoregional treatments or novel targeted agents. Furthermore, we delve into the critical search for predictive biomarkers, encompassing liquid biopsy and multi-omics approaches, and dissect the complex cellular and molecular mechanisms underlying therapeutic resistance within the immunosuppressive tumor microenvironment. Finally, we outline future translational directions, emphasizing the expansion of immunotherapy, the development of tailored strategies for therapy-resistant disease, and the imperative move towards a personalized, biomarker-driven treatment framework. This review provides a cohesive overview of the field and charts a roadmap for future research to overcome the current challenges in HCC immunotherapy.

PMID:41905572 | DOI:10.1016/j.critrevonc.2026.105305

J Proteome Res. 2026 Apr 3;25(4):2014-2023. doi: 10.1021/acs.jproteome.5c00983. Epub 2026 Mar 17.

ABSTRACT

OBJECTIVE: 19-Hydroxybufalin (19-H) is a natural bioactive compound with anticancer potential, but its molecular target and mechanism of action remain unclear. This study aimed to systematically evaluate its antigastric cancer activity and identify potential molecular targets.

METHODS: The antitumor effect of 19-H was evaluated in both in vitro and in vivo models. Multiomics analysis, thermal proteome profiling, molecular docking, and molecular dynamics simulations were employed to elucidate the mechanism of action. Functional assays were further conducted to validate the key target.

RESULTS: 19-H exhibited nanomolar-level inhibitory activity against various gastric cancer cell lines, significantly suppressing tumor growth in subcutaneous xenograft and patient-derived xenograft models. Multiomics analysis revealed that 19-H reshaped metabolic pathways in gastric cancer. TPP screening identified PLPP2 as a potential target with significantly increased thermal stability upon 19-H treatment. Molecular simulations further revealed that 19-H binds stably to the α-helical region of PLPP2.

CONCLUSIONS: 19-H exerts its antigastric cancer effect by targeting PLPP2 and remodeling the metabolic network. PLPP2 may represent a novel therapeutic target for gastric cancer.

PMID:41842934 | DOI:10.1021/acs.jproteome.5c00983