Oncogenic KRAS drives immune evasion through adenosine metabolic reprogramming mediated by NT5E and ADA

KRAS-mutant cancers are often resistant to immunotherapy and represent a major clinical challenge. The metabolic mechanisms by which oncogenic KRAS promotes immune evasion remain poorly defined. Using inducible KRAS cell models, human tumor specimens, and syngeneic mouse models, we combined metabolomic profiling, immune–tumor co-culture assays, and in vivo therapeutic studies to define how KRAS reshapes the tumor immune microenvironment. Adenosine metabolism was quantified by LC–MS/MS, immune infiltration was assessed by flow cytometry and immunohistochemistry, and therapeutic targeting was evaluated using genetic, enzymatic, and pharmacologic approaches. We identify adenosine accumulation as a key metabolic mechanism of KRAS-driven immune evasion. Oncogenic KRAS coordinately increases adenosine production through BRAF-dependent upregulation of ecto-5′-nucleotidase (NT5E) and suppresses adenosine clearance through AKT-mediated downregulation of adenosine deaminase (ADA). These complementary alterations result in pathological adenosine accumulation within the tumor microenvironment, thereby impairing T-cell function and promoting immune evasion. Genetic silencing of NT5E or enzymatic depletion of adenosine using ADA nanoparticles restored antitumor immunity and potentiated the efficacy of PD-1 blockade in vivo. Mechanistically, ADA converted the immunosuppressive metabolite adenosine into the immune-stimulatory metabolite inosine, thereby reprogramming the tumor immune milieu. In addition, pharmacologic inhibition of the adenosine receptor A2AR suppressed tumor growth in vivo by simultaneously enhancing immune activation and directly impairing KRAS-driven cancer cell viability. Our study uncovers a previously unrecognized KRAS-controlled adenosine metabolic axis that drives immune evasion. Targeting this pathway through ADA supplementation, NT5E inhibition, or A2AR blockade represents a rational strategy to overcome immunotherapy resistance with potential to improve the clinical outcomes in KRAS-driven cancers.