Abstract <p>The abscopal effect (AE) in oncology, where localized radiation therapy (RT) triggers a systemic anti-tumor immune response, holds great promise for revolutionizing cancer treatment. Emerging evidence suggests microRNAs (miRNAs), small non-coding RNAs, are essential in mediating the intricate interactions among the tumor, immune system, and tumor microenvironment underlying the AE. miRNAs, both within the tumor and circulating as exosomal cargo, can regulate gene expression to modulate the tumor microenvironment, enhance antigen presentation, and activate anti-tumor immunity. This miRNA-mediated intercellular communication can influence the radiation response, including tumor radiosensitivity, DNA damage repair, and apoptosis. Targeting specific miRNAs or leveraging miRNA-based therapies may sensitize tumors to radiation-induced immune responses, leading to more robust and durable AEs. Understanding the epigenetic regulation of the AE by miRNAs offers novel strategies to harness this phenomenon for improved cancer outcomes. Exploring the intersection of miRNAs, radiation, and the immune system holds the promise of developing more effective, personalized radiotherapy approaches that can unleash the body's defenses against metastatic disease. Unlocking the power of miRNA-mediated signaling may be the important key to unlocking the full potential of AE in the field of cancer treatment.</p> Graphical abstract <p>The graphical abstract offers a summary of our comprehensive review, focusing on the abscopal effect mechanism and the potential of diverse strategies, including miRNA delivery, cell therapy, and immunotherapy, to enhance this phenomenon for improved cancer treatment outcomes. Various mechanisms are illustrated surrounding the central focus, including miRNA delivery, cell therapy, and immunotherapy. One of the mechanisms depicted involves the delivery of miRNAs, which can modulate gene expression and immune responses, thereby amplifying the abscopal effect. Another approach highlighted is cell therapy, which involves the infusion of genetically engineered cells to enhance anti-tumor immunity and augment the abscopal effect. Lastly, immunotherapy is portrayed as a pivotal strategy for boosting the abscopal effect. Immunotherapeutic interventions, such as immune checkpoint inhibitors or cancer vaccines, can activate and potentiate the immune system's ability to recognize and eradicate tumor cells both locally and systemically.</p>