Hepatocellular carcinoma (HCC) is a lethal malignancy with the lack of effective treatments particularly for the disease at advanced stage. Even though immune checkpoint inhibitors (ICIs) have made a great progress in the treatment of HCC, enduring and ideal clinical benefits still cannot be achieved in a plenty of patients with HCC. Therefore, novel and refined combinations of ICIs are needed for enhancing the therapeutic effect. The latest study has reported that CAXII inhibitor (CAXIIi), as a novel type of anticancer drug, can modify immunosuppressive stress mediated by hypoxic/acidic metabolism, and regulate the expression of CCL8 by mediating the functions of monocytes and macrophages, consequently improving anti-tumor immunity and enhancing the therapeutic effect of PD-1 inhibitor in HCC, which shines a light on improving combined immunotherapy. This perspective aims to ignite enthusiasm to explore the application of CAXIIis with solid anti-tumor efficacy in combination with immunotherapy for HCC and related mechanisms.