Viroimmunotherapy in 9p21.3-deleted gliomas

One of the most frequent genetic alterations in high-grade gliomas is the homozygous deletion of the 9p21.3 chromosomal region, affecting 20-50% of tumors. The 9p21.3 locus encodes key tumor suppressor genes (CDKN2A and CDKN2B), MTAP, and a cluster of type I interferon (IFN) genes. The loss of CDKN2A and CDKN2B deregulates the Rb and p53 pathways, driving uncontrolled proliferation and creating a replication-permissive state that oncolytic viruses can exploit. The simultaneous deletion of MTAP and type I IFN genes impairs innate immune surveillance, thereby enhancing viral replication but limiting the host’s capacity for adaptive immune priming. Hence, current evidence suggests that 9p21.3 deletions eliminate a proliferative block and promote immune evasion, contributing to tumorigenesis. Despite the high frequency of 9p21.3 loss in malignant gliomas, the extent to which this deletion affects the therapeutic efficacy of oncolytic viruses remains unclear. In this review, we discuss the potential of using 9p21.3 status as a biomarker of therapeutic response, the challenges of modeling 9p21.3 loss in preclinical glioma models, and future strategies to exploit oncolytic viral permissiveness while stimulating antitumor immunity in patients with high-grade gliomas and 9p21.3 loss.