Adenosine is an immunosuppressive factor in the tumor microenvironment mainly through activation of the A<sub>2A</sub> adenosine receptor (A<sub>2A</sub>R), which is a mechanism hijacked by tumors to escape immune surveillance. Small-molecule A<sub>2A</sub>R antagonists are being evaluated in clinical trials as immunotherapeutic agents, but their efficacy is limited as standalone therapies. To enhance the antitumor effects of A<sub>2A</sub>R antagonists, dual-acting compounds incorporating A<sub>2A</sub>R antagonism and histone deacetylase (HDAC) inhibitory actions were designed and synthesized, based on co-crystal structures of A<sub>2A</sub>R. Compound <b>24e</b> (IHCH-3064) exhibited potent binding to A<sub>2A</sub>R (<i>K</i><sub>i</sub> = 2.2 nM) and selective inhibition of HDAC1 (IC<sub>50</sub> = 80.2 nM), with good antiproliferative activity against tumor cell lines in vitro. Intraperitoneal administration of <b>24e</b> (60 mg/kg, bid) inhibited mouse MC38 tumor growth with a tumor growth inhibition rate of 95.3%. These results showed that dual-acting compounds targeting A<sub>2A</sub>R and HDAC are potentially immunotherapeutic agents that are worth further exploring.