Inflammation‐triggering Engineered Macrophages (MacTriggers) Are Promising Cell‐based Therapeutic Avenues for Chemoresistant Solid Tumors

Background/Aim: Chimeric antigen receptor T‑cell therapy has shown efficacy against chemoresistant B‑cell leukemia and lymphoma but is limited in solid tumors. This study proposes using inflammation‑triggering engineered macrophages (MacTriggers) to target chemoresistant tumors. Intravenous MacTriggers infiltrate tumors, inducing inflammation via tumor necrosis factor‑alpha (TNF‑α), converting the immunosuppressive microenvironment into an immuno‑active state, and enhancing anti‑tumor immune responses. Materials and Methods: DOX‑resistant murine colon cancer cells (DOX‑Resi) were established by repeated in vivo exposure to DOX. IC₅₀ values and mRNA expression of Abcb1a (encoding P‑gp) in WT or DOX‑Resi cells were evaluated by qPCR. MacTriggers were engineered to release TNF‑α upon sensing tumor‑associated arginase 1 (Arg1) activity. BALB/c mice with subcutaneous DOX‑Resi tumors received intravenous MacTriggers or DOX. Tumor growth, histological changes, and side effects, including cardiotoxicity, were assessed via tumor volume monitoring, immunohistochemistry, and serum cardiac troponin‑I measurement. Results: DOX‑Resi cells had an IC₅₀ value approximately 2.5 times higher than WT cells, with significantly higher Abcb1a expression. MacTriggers significantly suppressed DOX‑Resi tumor growth, while DOX showed limited efficacy. MacTrigger administration did not cause severe side effects, unlike DOX, which induced cardiotoxicity. Conclusion: MacTriggers offer a novel, effective, and safer therapeutic approach for chemoresistant solid tumors, addressing chemotherapy limitations and improving outcomes in drug‑resistant cancers.