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Because PGE\u2082 is a critical driver of cancer progression and tumor immune evasion, this has motivated interest in combining NSAIDs with chemotherapy or immunotherapy for cancer treatment. However, since COX and PGE\u2082 levels vary across tumor types, it remains unclear whether tumor PGE\u2082 abundance solely dictates tumor response to NSAID-based therapies. Here, we investigated the therapeutic potential of indomethacin (Indo), a prototypical NSAID, in combination with cyclophosphamide (CTX), a widely used chemotherapeutic agent with immunostimulatory properties. Metronomic administration of Indo significantly enhanced the antitumor efficacy of CTX in multiple murine tumor models exhibiting variable COX2 and PGE\u2082 levels, including CT26, MC38, 4T1 and A20. The antitumor effects of CTX+Indo required CD8\u207a T cells and T-cell trafficking from tumor-draining lymph nodes and were further potentiated by anti-PD-1 blockade. Single-cell RNA sequencing (scRNA-seq) revealed that responsive CT26 tumors exhibited a reprogrammed tumor immune microenvironment (TIME), marked by increased effector CD8\u207a T-cell infiltration, reduced immunosuppressive myeloid populations, and enhanced interferon signaling in tumor cells. Importantly, Indo retained therapeutic benefit following CTX even in tumors incapable of producing PGE\u2082, demonstrating a critical contribution of COX-independent mechanisms, particularly inhibition of tumor-intrinsic oncogenic RAS signaling, to the enhanced efficacy of the CTX+Indo combination. Collectively, our results provide strong preclinical rationale for leveraging the COX\/PGE\n                  <jats:sub>2<\/jats:sub>\n                  and RAS dual inhibitory capacities of NSAIDs to enhance the efficacy of chemotherapy and immunotherapy.\n                <\/jats:p>","DOI":"10.64898\/2026.01.07.698231","type":"posted-content","created":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T21:05:19Z","timestamp":1767906319000},"source":"Crossref","is-referenced-by-count":1,"title":["Indomethacin exerts both cyclooxygenase inhibition-dependent and independent mechanisms to enhance chemo-immunotherapy in mice"],"prefix":"10.64898","author":[{"given":"Ogacheko D.","family":"Okoko","sequence":"first","affiliation":[{"name":"Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nada S.","family":"Aboelella","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The University of Chicago, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Ye","sequence":"additional","affiliation":[{"name":"Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Wang","sequence":"additional","affiliation":[{"name":"Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samson E.","family":"Simon","sequence":"additional","affiliation":[{"name":"Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md Yeashin","family":"Gazi","sequence":"additional","affiliation":[{"name":"Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor J.","family":"Enriquez Castro","sequence":"additional","affiliation":[{"name":"Immunology Center of Georgia at Augusta University, Augusta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mercy","family":"Kehinde-Ige","sequence":"additional","affiliation":[{"name":"Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlin","family":"Brandle","sequence":"additional","affiliation":[{"name":"Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongwen","family":"Lv","sequence":"additional","affiliation":[{"name":"Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David 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