BACKGROUND
Advanced urological tumors, particularly renal cell carcinoma (RCC), urothelial carcinoma (UC), and prostate cancer, remain a major source of cancer morbidity and mortality. Although immune checkpoint inhibitors (ICIs) have reshaped the management of advanced disease, most patients experience limited or non-durable clinical benefit due to primary or acquired resistance.
AIM
of the review. To summarize the major phenotypes and mechanisms of immunotherapy resistance in advanced urological tumors, and outline mechanism-based strategies that may restore sensitivity and improve the durability of response. Key scientific concepts of the review. Immunotherapy resistance is the result of the interplay between tumor-intrinsic alterations, the tumor microenvironment (TME), and host-related systemic determinants. Tumor-intrinsic mechanisms include low tumor antigenicity, defects in antigen processing and presentation pathways, and lineage-specific oncogenic programs such as the von Hippel-Lindau-hypoxia-inducible factor (VHL-HIF) signaling axis in RCC, fibroblast growth factor receptor (FGFR) pathway activation in UC, and androgen receptor (AR)-driven immune suppression in prostate cancer. Microenvironmental resistance is driven by suppressive myeloid and regulatory lymphoid populations, inhibitory cytokine and metabolic circuits, abnormal vasculature, fibrosis, and adaptive upregulation of alternative immune checkpoints. Host factors, including baseline immune competence, human leukocyte antigen (HLA) diversity, and the gut microbiome, further shape treatment efficacy. On this basis, current reversal strategies include multi-checkpoint blockade, rational combinations with targeted agents, chemo-/radio-immunotherapy, TME reprogramming, and microbiome-directed interventions, ideally guided by biomarkers and multi-omics stratification.
CONCLUSION
Overall, immunotherapy resistance in urological malignancies is a multifactorial and dynamic process involving tumor, microenvironmental, and host determinants. A comprehensive, mechanism-driven approach integrating biomarker-guided strategies and combination therapies is essential to improve clinical outcomes and achieve durable responses.
Pinying Wang, Bohan Zhang, Yaxing Shi et al.· Journal of Advanced Research· 1 citation
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
Breast, ovarian, cervical, and endometrial malignancies remain major causes of cancer-related morbidity and mortality due to metastatic progression, immune evasion, and the limited durability of therapeutic responses. Although immune checkpoint inhibitors have improved outcomes in selected patients, their efficacy is frequently constrained by profoundly immunosuppressive tumor microenvironments (TMEs). This review summarizes the molecular mechanisms driving immune resistance across these malignancies and highlights emerging strategies to improve immunotherapeutic efficacy. The roles of classical and emerging immune checkpoints, including Programmed cell death receptor 1 (PD-1), Programmed cell death-ligand 1 (PD-L1), T-cell immunoglobulin and mucin domain 3 (TIM-3), Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), Lymphocyte-activation gene 3 (LAG-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), V-domain Ig suppressor of T-cell activation (VISTA), and Siglec-mediated glyco-checkpoints, are discussed in the context of T-cell dysfunction and tumor immune escape. Mechanisms regulating immune cell infiltration, including chemokine signaling, stromal remodeling, and cytokine networks, are also examined for their contributions to immune exclusion or activation within the TME. Furthermore, metabolic reprogramming pathways, including lactate accumulation, adenosine signaling, and tryptophan catabolism, are evaluated for their roles in suppressing antitumor immunity and promoting tumor progression. The therapeutic potential of epigenetic modulation to restore antigen presentation, interferon signaling, and immune responsiveness is also highlighted. Finally, advances in antibody-drug conjugates, cancer vaccines, and adoptive cellular therapies are discussed as promising strategies that combine targeted cytotoxicity with immune activation. Overall, these insights support biomarker-driven combination therapies to overcome immune resistance and improve durable clinical outcomes in breast and gynaecological malignancies.
Vivek Uttam, Sia Daffara, Sandeep Singh et al.· Biochemical Pharmacology· 0 citations