The introduction of Low-Dose Radiation Therapy (LDRT) as an immunomodulatory tool with the potential to impact a broad spectrum of diseases, not limited to cancer, presents a promising avenue for medical research (19–25). Beyond its known role in cancer treatment, there's growing evidence that LDRT can modulate immune responses, which may be particularly relevant in non-oncological conditions like COVID-19. By stimulating the immune system, LDRT has shown potential in enhancing therapeutic outcomes (19–25).
One of the key immune-related pathways influenced by LDRT involves the CXCR3 ligand axis, including CXCL9, CXCL10, and CXCL11, which play a crucial role in recruiting immune cells expressing the CXCR3 receptor to tumor tissues. These immune cells, such as Th1 cells, CD8 T cells, and NK cells, are critical in the anti-tumor immune response. Several studies have demonstrated that the intratumoral injection of CXCL9, CXCL10, and CXCL11 can effectively attract these immune cells and inhibit tumor progression in various cancer types (26–28). Increased expression of these chemokines in tumor tissues has been associated with better clinical outcomes in patients with malignancies, emphasizing their role in anti-tumor immunity (26, 28). LDRT has been found to boost the levels of these chemokines, potentially increasing the infiltration of effector T cells into tumor tissues, thereby enhancing the local immunological milieu and suppressing tumor growth.
Moreover, the impact of low-dose whole-body irradiation extends beyond its direct killing effect on tumor cells. It has the remarkable ability to trigger both innate and adaptive anti-cancer immune responses. This includes the activation of immune cells such as T, B, and NK lymphocytes and macrophages, while simultaneously reducing the presence of immunosuppressive regulatory T cells (Treg) within the tumor microenvironment (30–31).
Studies on low-dose radiotherapy have highlighted the significance of dosage and dose rate. The selection of radiation dosage in the range of 1 Gy to 2 Gy, primarily targeting metastatic sites, has been shown to increase effector T-cell infiltration, facilitate M1 macrophage polarization, promote NK cell infiltration, and reduce TGF-β levels (32). Lower doses in the range of 0.5 Gy to 1 Gy allow for irradiation of larger body areas, enhancing anti-tumor immune responses. Clinical trials using ultra-low levels of ionizing radiation (0.1–0.2 Gy) have demonstrated remission rates and side effect profiles comparable to or better than other systemic anti-tumor modalities, underlining the effectiveness of whole-body low-dose radiation (29–33).
A crucial element in the immune system's response to low-dose irradiation is interferon (IFN) production. IFN, a multifaceted cytokine, plays a central role in regulating various biological functions, including cell proliferation, innate and adaptive immunity, and angiogenesis. Low-dose irradiation has been associated with the release of IFN, with its production linked to both radiation dosage and dose rate (33). IFN, in turn, influences the expression of chemokines like CXCL9 and CXCL10 (25–29), which draw immune cells, particularly CD8 T cells and NK cells, into tumor tissues, inhibiting tumor progression (34–35). The intricate feedback loop between IFN and immune cell recruitment underscores the critical role of IFN in tumor immunology.
One key orchestrator of IFN production is Interferon Regulatory Factor 7 (IRF7), which has been recognized as a significant prognostic factor in several cancer types. In various studies, IRF7 has demonstrated tumor-suppressing properties by modulating immune cells, influencing the tumor microenvironment, and increasing IFN production (36–38). IRF7's impact on type I IFN regulation leads to immune microenvironment shifts, from immunosuppressive to anti-tumor dominance (38). However, IRF7's behavior is context-dependent, as it can exhibit both tumor-promoting and tumor-suppressing properties, depending on the specific tumor-associated immune system (TAIS) dynamics (39–45).
In our research, we observed that low-dose irradiation upregulated IRF7 levels, which in turn contributed to elevated IFN production in tumor tissues. This effect was consistent with previous studies that identified IRF7's role in enhancing IFN levels and its association with tumor suppression (36–38). Furthermore, immunofluorescence analysis confirmed that low-dose irradiation promoted nuclear translocation of IRF7, enabling its interaction with IFN-related processes.
Our findings suggest that LDRT, through its modulation of IRF7 and IFN production, can restore the equilibrium between the immune system and tumor cells within the TAIS, a balance often disrupted during cancer development (46). By enhancing the immune milieu, particularly by increasing the recruitment of immune effector cells through chemokines, LDRT has the potential to shift the TAIS back into an "elimination" phase, where immune-mediated tumor control can be restored.
Furthermore, combining LDRT with other therapies, such as immunotherapy or chemotherapy, offers an intriguing approach. Several clinical studies have shown promising outcomes when LDRT is combined with other treatments (41–46). In our study, the combination of systemic low-dose radiation with a CTLA-4 checkpoint inhibitor had a synergistic anti-tumor effect in a mouse model, indicating the potential for combination therapies.
In conclusion, LDRT's immunomodulatory effects through IRF7 and IFN induction, coupled with the recruitment of immune effector cells via chemokines, hold promise for enhancing anti-tumor immune responses and potentially extending LDRT's applications beyond cancer. The context-dependent role of IRF7 in different TAIS scenarios necessitates further research to elucidate the full extent of LDRT's impact on immune dynamics. This work contributes to the growing body of evidence supporting the potential of LDRT as an immunomodulatory tool in managing a wide range of diseases, not limited to cancer. By restoring immune-tumor equilibrium, LDRT offers a novel approach to reinvigorate immune-mediated tumor control, providing renewed hope for patients battling various malignancies and other diseases.