Plants contain underutilized resources of compounds that can be employed to combat viral diseases. Aloe vera (L.) Burm. f. (syn. Aloe barbadensis Mill.) has a long history of use in traditional medicine, and A. vera extracts have been reported to possess a huge breadth of pharmacological activities. Here, we discuss the potential of A. vera compounds as antivirals and immunomodulators for the treatment of viral diseases. In particular, we highlight the use of aloe emodin and acemannan as lead compounds that should be considered for further development in the management and prevention of viral diseases. Given the immunomodulatory capacity of A. vera compounds, especially those found in Aloe gel, we also put forward the idea that these compounds should be considered as adjuvants for viral vaccines. Lastly, we present some of the current limitations to the clinical applications of compounds from Aloe, especially from A. vera.

FDA-approved oncolytic herpes simplex virus-1 (oHSV) therapy has emerged as a promising 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. A deeper understanding of the molecular mechanisms underlying resistance to oHSV is 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 Insulin-like growth factor 1 receptor (IGF1R) signaling drives 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 have shown limited cytotoxicity, its combination with oHSV led to a modest but significant increase in cytotoxicity across tested breast cancer (BC) and primary glioblastoma (GBM) cells in vitro 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 nuclear localization, and significantly enhanced survival in orthotopic BC and GBM models. Collectively, these findings identify the IGF1R/YAP1 axis as a critical driver of resistance to oHSV and RTx and provide a strong rationale for the clinical evaluation of this triple-combination strategy to enhance therapeutic efficacy in patients with BC and GBM.

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.