The controversy lies in the coexistence of “tumor‐promoting” and “tumor‐suppressing” conclusions in different studies: Activation of H2R can enhance NK cell activity, promote DC maturation and Th1 polarization, exerting antitumor effects; however, activation of the same receptor on Treg cell promotes immune escape; while H1R blockade can enhance the efficacy of immune checkpoints in some models. This evidence concerns the gene HRH2 and neoplasm.