In our previously reported phase 2 and phase 3 studies, the combination of short-course radiotherapy and neoadjuvant immunochemotherapy (SIC) is established as effective cancer therapies for locally advanced rectal cancer (LARC). Here, we apply multi-omic analyses to paired pre- and post-treatment LARC specimens undergoing SIC. The peripheral blood-derived TREM1+ mono-macrophage subsets that display a pro-inflammatory phenotype are identified and correlate with complete response to SIC. Mechanically, ionizing radiation (IR) induces peripheral TREM1+ mono-macrophage expansion in tumors. Following IR, the loss of TREM1 in mono-macrophages undermines antitumor immunity by altering mono-macrophage differentiation and inhibiting CD8+ T cell infiltration and activation. The TREM1+ mono-macrophage response may rely on activation of key inflammatory pathways, including nuclear factor κB (NF-κB) signaling and Toll-like receptor pathway. Pharmacological inhibition of TREM1 signaling abolishes IR-induced immunoactivation and reduces combined IR and/or anti-PD-1 treatment. Thus, we establish a crucial role of a mono-macrophage state in mediating effective cancer therapy.