Inducing ferroptosis in hepatocellular carcinoma (HCC) cells represents an important therapeutic strategy, but intrinsic resistance mechanisms often limit efficacy. Therefore, elucidating the mechanisms underlying ferroptosis resistance in HCC cells can facilitate the development of effective therapeutic strategies. Here, we performed genome-wide CRISPR/Cas9 library screens to identify TRIM27 as a key determinant of ferroptosis resistance. TRIM27 knockdown markedly potentiated erastin-induced ferroptosis in HCC cells, whereas TRIM27 overexpression suppressed the expression of fatty-acid metabolic enzymes including ACSL4 and reduced oxidized lipid accumulation. Mechanistically, TRIM27 directly binds with ACSL4 and promotes its K48-linked ubiquitination and degradation, thereby attenuating ferroptosis in HCC cells. Furthermore, we developed TRIM27-Cas9-loaded EVs with robust editing efficiency. These engineered EVs were readily internalized by HCC cells and preferentially accumulated in the liver. Functionally, TRIM27-Cas9-loaded EVs inhibited HCC cell proliferation by enhancing ACSL4-mediated ferroptosis and significantly improved the anti-tumor efficacy of anti-PD-1 therapy in HCC. Collectively, our findings suggest that TRIM27 confers ferroptosis resistance via facilitating K48-linked ubiquitination and subsequent proteasomal degradation of ACSL4. TRIM27-Cas9-loaded EVs restore cellular sensitivity to ferroptosis, inhibit HCC proliferation, and sensitize HCC lesions to anti-PD-1 immunotherapy.
Jie Wen, Zhihui Wang, Zhirui Zeng et al.· Cell Death and Differentiati...· 0 citations
KRAS mutations are among the most prevalent oncogenic drivers in human malignancies and are increasingly recognized as critical determinants of tumor progression, immune evasion, and therapeutic resistance. Beyond its canonical role in promoting oncogenic signaling, accumulating evidence indicates that KRAS functions as a regulator of the tumor immune microenvironment, influencing antigen presentation, inflammatory signaling, metabolic adaptation, stromal remodeling, and responsiveness to immunotherapy. This review synthesizes current knowledge regarding the biological and immunological consequences of oncogenic KRAS across major cancer types, including non-small cell lung cancer, colorectal cancer, and pancreatic ductal adenocarcinoma, with emphasis on the mechanisms by which KRAS-driven tumors establish and maintain immunosuppressive microenvironments. Recent advances in immunopeptidomics and precision immuno-oncology have identified KRAS-derived neoantigens that can be targeted through T-cell receptor-engineered therapies, bispecific antibodies, and therapeutic vaccines. Concurrently, the clinical development of direct KRAS inhibitors, including sotorasib and adagrasib, has demonstrated meaningful antitumor activity while revealing adaptive resistance mechanisms that frequently limit durable responses. Emerging evidence suggests that effective therapeutic strategies will require integrating KRAS-targeted therapies with immune checkpoint blockade and other immunomodulatory approaches to overcome tumor-intrinsic and microenvironment-mediated resistance. Collectively, current evidence supports a paradigm in which KRAS functions not only as an oncogenic driver but also as a regulator of tumor-immune interactions, shaping therapeutic responsiveness and providing opportunities for biomarker-guided and combination-based immunotherapy in KRAS-mutant cancers.
M. Ashrafizadeh, Noushin Nabavi, Yifei Xu· Cancer Biome and Targeted Th...· 0 citations