Human endogenous retrovirus H long terminal repeat-associating protein 2 (HHLA2 or B7-H7) is a newly discovered B7 family member. HHLA2 is aberrantly expressed in solid tumors and exerts co-stimulatory or co-inhibitory activities dependent on interaction with counter receptors. HHLA2 represents co-stimulatory effects upon interaction with transmembrane and immunoglobulin domain containing 2 (TMIGD2, also called CD28H), but its interaction with killer cell Ig-like receptor, three Ig domains and long cytoplasmic tail 3 (KIR3DL3) renders co-inhibitory effects. TMIGD2 is mainly expressed on resting or naïve T cells, whereas expression of KIR3DL3 occurs on activated T cells. HHLA2/KIR3DL3 attenuates responses from both innate and adaptive anti-tumor immunity, and the activity within this axis is regarded as a biomarker of weak prognosis in cancer patients. HHLA2/KIR3DL3 promotes CD8⁺ T cell exhaustion and induces macrophage polarity toward pro-tumor M2 phenotype. HHLA2 represents diverse expression profile and activity in tumor and stroma. Tumoral expression of HHLA2 is presumably higher compared with programmed death-ligand 1 (PD-L1), and HHLA2 co-expression with PD-L1 is indicative of more severe outcomes. A suggested strategy in patients with HHLA2^high cancer is to use monoclonal antibodies for specifically suppressing the HHLA2 inhibitory receptor KIR3DL3, not the HHLA2 ligand. TMIGD2 can be a target for development of agonistic bispecific antibodies for hampering tumor resistance to the programmed death-1 (PD-1)/PD-L1 blockade therapy.