Therapy-induced IGF1R signaling as an actionable vulnerability in oncolytic virotherapy

Oncolytic herpes simplex virus 1 (oHSV) is a promising viro-immunotherapy that directly lyses tumor cells while reshaping the tumor microenvironment (TME) and stimulates anti-tumor immunity. However, despite encouraging preclinical and clinical activity, treatment-induced adaptations in tumor cells and the surrounding microenvironment can promote survival, repair, repopulation, immune escape, and recurrence, thereby limiting durable therapeutic benefit. In our recent article published in Cell Death & Disease,¹ we asked why oHSV often fails to achieve durable tumor control and whether the adaptive resistance it induces can be therapeutically overcome. Building on our previous finding that oHSV treatment induces insulin-like growth factor 2 (IGF2) secretion from cancer cells,² we showed that this response drives a compensatory survival program centered on the IGF1 receptor (IGF1R). This adaptive IGF1R response was further enhanced when virotherapy was combined with radiotherapy. Importantly, targeting IGF1R overcame this treatment-induced resistance and enhanced the efficacy of combined oHSV and radiotherapy.

We investigated this question in glioblastoma (GBM) and breast cancer (BC) models with strong resistance phenotypes. In both tumor models, compensatory signaling pathways can enable residual tumor cells to survive and repopulate after treatment. This challenge is particularly pronounced in GBM, where infiltrative tumor cells extend into surrounding brain tissue and recurrence is nearly universal. These complementary models allowed us to determine whether a common, treatment-induced resistance mechanism could be identified and therapeutically exploited.

We first showed that oHSV activates IGF1R signaling in tumor cells both in vitro and in vivo. This signaling supported tumor cell proliferation and survival after oHSV therapy, suggesting that oHSV unintentionally engages a feedback circuit that helps residual disease persist. IGF1R inhibition alone produced limited cytotoxicity, consistent with the mixed clinical performance of IGF1R-targeted monotherapies. However, combining IGF1R blockade with oHSV produced a modest but significant increase in anti-tumor activity across BC and primary GBM models, demonstrating that therapy-induced IGF1R signaling is functionally relevant and therapeutically targetable. This finding became even more compelling when we considered radiotherapy, a standard treatment modality frequently combined with other treatments in neuro-oncology and metastatic disease. Radiotherapy can enhance tumor antigen release and influence anti-tumor immunity, but it can also activate stress-response programs that promote resistance. Previous studies have shown that radiotherapy induces IGF1 secretion and subsequent IGF1R activation, suggesting a shared mechanism of resistance with oHSVs.^3,4

Although this study initially focused on IGF1R, we found that Yes-associated protein 1 (YAP1) also contributes to the adaptive response. In our models, exposure to oHSV and radiotherapy, either alone or in combination, increased YAP1 activation and nuclear localization. YAP1 is increasingly recognized as a central regulator of tumor cell plasticity, proliferation, survival, and therapy resistance across tumor types.⁵ Persistent nuclear YAP1 promotes transcriptional programs that enable tumor cells to withstand cytotoxic therapy, maintain stemness features, and remodel the microenvironment in ways that favor immune evasion. Dual therapy with IGF1R inhibition and either oHSV or radiotherapy reduced YAP1 activation but did not fully suppress its nuclear localization. This incomplete inhibition likely reflects the complex regulation of YAP1 by mechanical cues, other receptor tyrosine kinases, and G protein-coupled receptors (GPCRs). The incomplete suppression of YAP1 may allow tumor cells to retain a core component of their adaptive response. Regardless, the convergence of both therapies on the IGF1R-YAP1 signaling axis activates a prosurvival and proliferative transcriptional program that blunts therapeutic efficacy and represents a targetable vulnerability in the context of combined oHSV and radiotherapy.

The therapeutic rationale therefore followed directly from these observations. If oHSV induces IGF1R signaling and radiotherapy further reinforces an IGF1R-YAP1-dependent resistant state, then simultaneous IGF1R blockade should enhance the effects of either monotherapy or, more importantly, dual therapy (Figure 1). Indeed, across orthotopic BC and GBM models, the triple combination of oHSV, radiotherapy, and IGF1R blockade produced synergistic anti-tumor effects and significantly extended survival. More importantly, despite the many redundant signals capable of sustaining YAP1 activity, adding IGF1R inhibition nearly abolished YAP1 expression and nuclear localization. These findings suggest that IGF1R functions as a shared, treatment-induced resistance node upstream of this adaptive program. IGF1R blockade was therefore most effective in the context of combined oHSV and radiotherapy, when tumor cells had become increasingly dependent on this compensatory adaptive pathway.

Figure 1. oHSV and radiotherapy induce IGF2 and IGF1 signaling, respectively, activating the IGF1R-YAP1 axis and promoting tumor survival, proliferation, angiogenesis, and immune suppression.

Triple combination therapy with IGF1R blockade disrupts this adaptive resistance signaling pathway, enhances tumor eradication, and improves therapeutic outcomes.

Our findings highlight two important considerations for the development of viro-immunotherapy. First, oHSV can induce adaptive signaling programs that support the survival of residual tumor cells, underscoring the need to define resistance mechanisms that emerge after treatment rather than focusing solely on baseline tumor characteristics. Second, targeting resistance pathways shared by oHSV and radiotherapy can substantially improve therapeutic efficacy. This approach enables the rational design of combination strategies that not only enhance tumor killing but also prevent treatment-induced tumor persistence and recurrence. Because each additional agent increases biological, operational, and clinical complexity, the most effective combinations may be those that intercept shared, treatment-induced resistance nodes rather than simply stacking therapies with independent mechanisms.

This framework may be particularly critical for brain tumors. GBM remains profoundly difficult to treat because recurrence is nearly universal and local therapies rarely eliminate infiltrative residual disease.^6,7 A strategy that couples direct oncolysis, radiotherapy, and suppression of therapy-induced resistance could help move the field toward more durable tumor control. Although additional translational studies are needed, our findings provide a strong rationale for repurposing previously developed orphaned IGF1R inhibitors in combination with oHSV and radiotherapy for treatment-resistant solid tumors.

This study also helps reframe IGF1R as a therapeutic target. IGF1R has traditionally been considered a constitutive, tumor-intrinsic dependency, yet clinical responses to single-agent inhibition have generally been limited. Our data suggest a different therapeutic opportunity: IGF1R is most valuable as a load-bearing context-dependent resistance node that becomes increasingly important after virotherapy and radiotherapy provoke compensatory survival signaling. In that sense, IGF1R is therapeutically relevant not simply because it is expressed but because treatment makes the tumor more dependent on it.

Oncolytic virotherapy remains a promising therapeutic platform, but realizing its full potential will require a deeper understanding of the adaptive programs it elicits. By identifying therapy-induced IGF1R signaling and its connection to YAP1 as a tractable resistance mechanism, our study provides a framework for combination strategies that are both mechanistically grounded and translationally actionable.