Overcoming IGF1R-Mediated Resistance to Oncolytic HSV1 and Radiotherapy via Triple Combination Therapy

FDA-approved oncolytic herpes simplex virus-1 (oHSV) therapy has emerged as an effective viro-immunotherapy for solid tumors. However, tumor- and tumor microenvironment (TME)-associated adaptations following viral treatment, such as feedback immune suppression, neoangiogenesis, and enhanced tumor aggressiveness, often hinder complete tumor eradication. Gaining a deeper understanding of the molecular mechanisms that limit the therapeutic efficacy of oHSV will be crucial to enhancing its clinical impact. We recently discovered that oHSV induces Insulin-like growth factor 2 (IGF2) secretion, shaping an immunosuppressive TME. Similarly, radiotherapy (RTx) activates the IGF1/IGF1R and YAP1 signaling pathways, further promoting therapeutic resistance. In this study, we investigated how oHSV-induced IGF1R/YAP1 signaling influences feedback pro-survival and proliferative pathways in tumor cells and evaluated the therapeutic potential of combining IGF1R blockade with oHSV and RTx. We first demonstrated that oHSV activates IGF1R signaling in vitro and in vivo, promoting tumor proliferation. While IGF1R-targeted monotherapies showed limited cytotoxic effects, combining IGF1R inhibitors with oHSV led to a significant, albeit modest, increase in cytotoxicity across tested in vitro breast cancer (BC) and primary glioblastoma (GBM) cells and in vivo xenograft models. Furthermore, we observed that co-treatment with oHSV and RTx robustly activated both IGF1R and YAP1 in resistant cells, revealing the IGF1R/YAP1 axis as a key mediator of resistance to dual oHSV and RTx therapy. Notably, the triple combination of oHSV, RTx, and IGF1R blockade yielded synergistic anti-tumor effects, abolished YAP1 expression, and significantly enhanced survival in orthotopic BC and GBM models. Collectively, these findings provide a strong rationale for the clinical evaluation of triple-combination therapy as a synergistic strategy to enhance the anti-tumor efficacy of oHSV and overcome RTx resistance in patients with BC and GBM.