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Based on hA 2A AR structures, a hydrophobic C8-heteroaromatic ring in 5'-truncated adenosine analogues occupies the subpocket tightly, converting hA 2A AR agonists into antagonists while maintaining affinity toward hA 3 AR. The final compounds of 2,8-disubstituted- N 6 -substituted 4'-thionucleosides, or 4'-oxo, were synthesized from d-mannose and d-erythrono-1,4-lactone, respectively, using a Pd-catalyst-controlled regioselective cross-coupling reaction. All tested compounds completely antagonized hA 2A AR, including 5d with the highest affinity ( K i,A 2A = 7.7 ± 0.5 nM). The hA 2A AR- 5d X-ray structure revealed that C8-heteroaromatic rings prevented receptor activation-associated conformational changes. However, the C8-substituted compounds still antagonized hA 3 AR. Structural SAR features and docking studies supported different binding modes at A 2A AR and A 3 AR, elucidating pharmacophores for receptor activation and selectivity. Favorable pharmacokinetics were demonstrated, in which 5d displayed high oral absorption, moderate half-life, and bioavailability. Also, 5d significantly improved the antitumor effect of anti-PD-L1 in vivo . Overall, this study suggests that the novel dual A 2A AR/A 3 AR nucleoside antagonists would be promising drug candidates for immune-oncology.