Abstract Radiation therapy (RT) is a major treatment modality for various forms of cancers including solid tumors and metastases. Recent advances found that the efficacy of RT, particularly for achieving curative and abscopal effects, is heavily dependent on the induction of anti-tumor T cell immunity, especially the tumoricidal activity of CD8 T cells. Despite that various strategies comprising fractionated radiation and/or combinatorial immune modulators have been explored to enhance the CD8 T cell activity in RT, preclinical studies and clinical trials thus far have attained suboptimal results, especially when tumors are well-established, large or are poorly immunogenic. In our preliminary studies, we tested whether depletion of SIRPα, a negative regulator of phagocytic leukocytes, would improve RT efficacy. The results were stunning; a single fraction of low-dose radiation (8Gy or 20Gy), which had no effect on tumor-burdened WT mice, led to complete responses and eliminated all traces of MC38 and Pan02 carcinoma tumors in Sirpα-/- mice – not only smaller tumors (< 200mm3) but also those of large sizes (> 400mm3). With this combinatorial strategy, we observed greatly enhanced CD8 T cell tumoricidal activities attributable to 1) successful early-stage Sirpα-/- phagocytes/APCs uptake and presentation of tumor antigens and subsequent tumor-specific T cell activation and tumor infiltration, and 2) marked reduction of immunosuppressive components, including Tregs, MDSCs and tumor expression of PD-L1, in the tumor microenvironment (TME) following RT. The RT-induced anti-tumor adaptive immunity in SIRPα-/- mice was further exhibited by abscopal effects that cleared distal tumors, resistance to future tumor engraftments and in recipient WT mice to which tumor-specific CD8 T cells were adoptively transferred. These preliminary results are profound, leading to the postulation that SIRPα interaction and signaling prominently inhibit the RT- induced immune response toward cancer and that SIRPα deficiency provides a new foundation for developing highly efficacious anti-tumor RT modalities. Our central hypothesis is that SIRPα deficiency steers RT to robustly activate tumor antigen presentation to lymphocytes and alter the TME to become non-tolerogenic, leading to enhanced T cell tumoricidal activity and long-lasting adaptive immunity. We will test this hypothesis by two aims: Aim 1 is to determine how depletion of SIRPα allows RT-activated APCs to robustly activate tumor- specific CD8 T cells and how this is suppressed by SIRPα signaling; Aim 2 is to determine the mechanism(s) by which RT induces an anti-tumor, non-tolerogenic TME in Sirpα-/- mice. Clearly, these studies point to extremely important knowledge and unprecedented cancer immunotherapy mechanisms, application of which will bring about revolutionary breakthrough in RT modalities for cancer eradication, as well as producing long-lasting effective adaptive immunity that exhibits abscopal effects a...