Abstract: Intrinsic or acquired chemo-resistance is the main reason for chemotherapy failure, and thus finding ways to reverse chemo-resistance has become an interesting topic for research. Studies have revealed that immunomodulatory molecules are involved in cancer chemo-resistance. Hence, interventions that target immunomodulatory molecules to reverse chemo-resistance have attracted a great deal of concern from domestic and foreign scholars. Immunomodulatory molecules, such as PD-L1, B7-H3, HMGB1, TRAIL, MyD88, and Cytokines (TNF-α, IFN-α, IL-6), have been proven to take part in regulating immune function and tumor drug-resistance characteristics, thereby providing new ideas to the reversal of tumor chemo-resistance. This artide reviews the progression of immuno-modulatory molecules with the change in cancer chemotherapy sensitivity to provide a theoretical basis for the application of new thera-peutic regimen of bio-chemotherapy.