Radiotherapy is a commonly used cancer treatment; however, patients with high serum squamous cell carcinoma antigen (SCCA1/SERPINB3) are associated with resistance and poor prognosis. Despite being a strong clinical biomarker, the modulation of SERPINB3 in tumor immunity is poorly understood. We investigated the microenvironment of SERPINB3 high tumors through RNAseq of primary cervix tumors and found that SERPINB3 was positively correlated with CXCL1/8, S100A8/A9 and myeloid cell infiltration. Induction of SERPINB3 in vitro resulted in increased CXCL1/8 and S100A8/A9 production, and supernatants from SERPINB3-expressing cultures attracted monocytes and MDSCs. In murine tumors, the orthologue mSerpinB3a promoted MDSC, TAM, and M2 macrophage infiltration contributing to an immunosuppressive phenotype, which was further augmented upon radiation. Radiation-enhanced T cell response was muted in SERPINB3 tumors, whereas Treg expansion was observed. A STAT-dependent mechanism was implicated, whereby inhibiting STAT signaling with ruxolitinib abrogated suppressive chemokine production. Patients with elevated pre-treatment serum SCCA and high pSTAT3 had increased intratumoral CD11b+ myeloid cell compared to patients with low SCCA and pSTAT3 cohort that had overall improved cancer specific survival after radiotherapy. These findings provide a preclinical rationale for targeting STAT signaling in tumors with high SERPINB3 to counteract the immunosuppressive microenvironment and improve response to radiation.