<p>Colorectal cancer progression is increasingly recognized as a process shaped not only by tumor-intrinsic genetic alterations but also by dynamic interactions within the tumor microenvironment. Tumor-associated macrophages represent a dominant immune population in colorectal tumors and exhibit remarkable functional plasticity in response to metabolic and immunological cues. Among these cues, extracellular nucleotide signaling has emerged as a critical regulator of macrophage behavior. Metabolic stress, hypoxia, and cell death within colorectal tumors promote the release of extracellular ATP, which is rapidly hydrolyzed by ectonucleotidases into adenosine. This ATP–adenosine axis functions as a molecular switch that transforms pro-inflammatory immune activation into sustained immunosuppression. This mechanistic review synthesizes current evidence delineating how dysregulated extracellular ATP metabolism and adenosine signaling reprogram tumor-associated macrophages toward immunosuppressive, tumor-supportive phenotypes in colorectal cancer. This review discusses the coordinated roles of ectonucleotidases, purinergic receptors, and hypoxia-driven signaling in shaping macrophage immunometabolic states. Particular emphasis is placed on adenosine receptor–mediated pathways that impair antigen presentation, suppress cytotoxic immune responses, and contribute to resistance against immunotherapy and chemotherapy. By integrating immunometabolism, purinergic signaling, and macrophage plasticity, this review highlights the ATP–adenosine axis as a central mechanism of immune evasion in colorectal cancer. This review further explores therapeutic strategies targeting this pathway as a means to reprogram macrophages and overcome tumor-induced immune suppression. Understanding these mechanisms may support the rational development of macrophage-centered interventions aimed at restoring effective antitumor immunity.</p>