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Head and neck squamous cell carcinoma (HNSCC) is a significant cause of morbidity and mortality worldwide, with limited treatment options for patients with locally advanced disease. CD47 immune checkpoint inhibitors have been used to block the CD47/SIRPa interaction that inhibits antigen-presenting cell phagocytosis, thereby enhancing antigen presentation to cytotoxic T-cells, and have shown promise in combination with anti-PD1 immunotherapy in tumors, including recurrent/metastatic HNSCC. We found that CD47 expression is associated with poor prognosis in HNSCC and explored the anti-tumor activity of an anti-CD47 fusion protein in combination with anti-PD1 and lymphatic-sparing radiotherapy in a locally advanced HNSCC model. In the 4MOSC1 syngeneic HPV-negative HNSCC mouse model, ALX301 (an engineered CD47-blocking SIRPα fusion for murine models) induced complete tumor regression when combined with anti-PD-1, and produced a partial tumor response as a monotherapy. An anti-PD1 immune checkpoint inhibitor in a CD47-null tumor background led to complete tumor regression confirming a key role for CD47 in tumor immunity. ALX301 treated mice demonstrated increased MHC-II expression on dendritic cells within the tumor and upregulation of CD86 co-stimulatory molecule on dendritic cells within the tumor, sentinel lymph nodes, and contralateral lymph nodes. Combination ALX301 and anti-PD1 treatment in an anti-PD1 resistant 4MOSC2 model demonstrated significant tumor regression, enhanced survivability, improved response with neoadjuvant radiotherapy, and greater retention of CD8 + T-cells within the tumor microenvironment. Notably, T-cell receptor sequencing revealed increased shared clonality between the tumor and sentinel lymph nodes of ALX301 treated mice. These data demonstrate that a combination of CD47 blockade and anti-PD1 therapy enhances tumor antigen presentation and immune cell infiltration, while further improving anti-tumor responses in combination with tumor-targeted radiotherapy. This study provides support for the rational design of combinatorial immunoradiotherapy, using anti-CD47 inhibitors and anti-PD1 therapy, in a clinical trial targeting locally advanced HPV-negative HNSCC.