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Background Radiotherapy (RT) is a cornerstone of cancer treatment, yet its efficacy is often limited by therapy-induced immunosuppression and tumor recurrence. One key contributor to this immunosuppressive tumor microenvironment (TME) is the reprogramming of tumor-associated macrophages (TAMs) toward an M2-like phenotype. However, the metabolic mechanisms driving this shift following RT remain poorly understood.Methods Murine colorectal cancer models (MC38 and CT26) were treated with a single high-dose RT (20 Gy) to examine immune and metabolic changes within the TME. Immune profiling and TAM polarization was performed using flow cytometry, immunohistochemistry, quantitative PCR, Western blotting and transcriptomic analyses. TAM metabolism was assessed via fatty acid uptake, mitochondrial potential, and expression of metabolic enzymes. Functional studies used pharmacologic inhibition (GW6471 for PPARα, etomoxir for fatty acid oxidation) and genetic knockout models, including macrophage-specific knockout of AMPKα and PPARα-deficient mice. Bone marrow chimera models and dual-luciferase assays were used to validate cell-intrinsic effects and transcriptional mechanisms in vivo.Results High-dose RT induced a pronounced immunosuppressive TME, characterized by depletion of effector T cells and expansion of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and M2-like TAMs. These TAMs exhibited increased fatty acid oxidation (FAO) and upregulated expression of CD36, PPARα, and CPT1α. Mechanistically, AMP-activated protein kinase α (AMPKα) acted upstream of PPARα, which directly transcriptionally activated CPT1α, driving FAO and M2 polarization. Inhibiting PPARα or FAO reprogrammed TAMs toward a less suppressive phenotype, restored CD8 + T cell function, and enhanced tumor control following RT. Bone marrow chimera studies confirmed the intrinsic role of PPARα in TAM-mediated immunosuppression. Luciferase assays verified direct transcriptional regulation of CPT1α by PPARα.Conclusions We identify a novel metabolic axis—CD36-AMPKα-PPARα-CPT1α—that promotes RT-induced M2 polarization of TAMs through enhanced FAO. This metabolic reprogramming contributes to immunosuppression and RT resistance. Targeting this pathway reverses TAMs polarization and improves RT efficacy, providing a rationale for combining metabolic inhibitors with RT to overcome tumor immune suppression.