The future of cancer therapy? Integrating oncolytic adenoviruses with epigetic modulation.

Therapeutic resistance remains a defining limitation in the management of advanced solid tumors, where conventional modalities including chemotherapy, radiotherapy, and immune checkpoint blockade often fail to achieve durable responses. Oncolytic adenoviruses (OAds) have emerged as tumor-selective and immunogenic platforms capable of inducing direct oncolytic and systemic antitumor immunity. However, their clinical efficacy is frequently constrained by intrinsic tumor resistance mechanisms, including impaired viral entry, antiviral immune responses, and immunologically "cold" tumor microenvironments. Epigenetic modulation represents a promising strategy to overcome these barriers by reprogramming chromatin accessibility, restoring antigen presentation, and enhancing viral permissiveness. This review explores the mechanistic and translational rationale for integrating OAds with epigenetic therapies, highlighting preclinical and clinical evidence supporting synergistic interactions. We further discuss the implications of this combinatorial approach for precision oncology and its potential to redefine therapeutic paradigms in resistant malignancies.