Copyright: © 2026 Yuzhalin. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Immunologically “cold” malignant tumors of the central nervous system (CNS) evade immune surveillance largely through downregulation or loss of major histocompatibility complex class I (MHC-I), impairing CD8+ T cell-mediated elimination and contributing to poor prognosis. I discuss multiple strategies to restore MHC-I expression in brain cancers, including epigenetic modulation with histone deacetylase (HDAC) and DNA methyltransferase inhibitors, adeno-associated virus (AAV)-based gene therapy for direct human leukocyte antigen (HLA) class I or transcription factor delivery, and modulation of the tumor microenvironment to enhance antigen presentation. In addition, targeting autophagy and addressing genetic HLA losses are discussed as critical considerations. Effective MHC-I restoration may require integrated approaches that also enhance antigen processing and neoantigen presentation. Overcoming CNS-specific barriers and combining MHC-I re-expression with immunotherapy and chemoradiotherapy could unlock new therapeutic avenues against CNS malignancies.
Copyright: © 2026 Crane et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. PURPOSE:The discovery of KRAS G12C as a therapeutic target has transformed oncology with the development of specific inhibitors. This study aimed to characterize the prevalence and clinicogenomic features of KRAS G12C mutations in genitourinary malignancies, an area with limited prior data despite recent FDA approvals of KRAS G12C-targeted therapies. MATERIALS AND METHODS:Comprehensive genomic profiling was performed on 13,654 formalin-fixed paraffin-embedded specimens, including 1,453 renal clear cell carcinomas (RCCC), 3,879 urothelial bladder carcinomas (UBC), and 8,322 prostate acinar adenocarcinomas (PAAC). Tumor mutational burden (TMB), microsatellite instability (MSI), and PD-L1 expression (Dako 22C3) were also assessed. RESULTS:KRAS alterations were identified in 7 RCCC (<1%), 202 UBC (5.2%), and 158 PAAC (1.9%) cases. KRAS G12C variants were detected in 0 RCCC (0%), 24 UBC (12%), and 1 PAAC (<1%) cases. No KRAS G12C-mutated tumors showed MSI-high status. In UBC, KRAS G12C-positive cases demonstrated significantly lower TERT co-mutations and higher KDM6A alterations compared to KRAS G12C-negative cases (both p < 0.05). Age and sex distributions were similar across subtypes. Predominant co-alterations included VHL, SETD2, and PBRM1 in RCCC, and TP53, CDKN2A, and TERT in UBC. CONCLUSIONS:KRAS G12C mutations occur infrequently in major genitourinary malignancies. However, given the expanding therapeutic landscape of KRAS G12C inhibitors and potential for basket trials, further investigation in bladder and prostate cancers is warranted. These agents may offer meaningful benefit to the small subset of patients harboring this actionable alteration.
