This study investigates the role of iRhom1 in chemoresistance and antitumor immunity, and develops a nanocarrier for co-delivering iRhom1 pre-siRNA and chemotherapy drugs to improve cancer treatment. iRhom1 is involved in cancer cell proliferation and negatively correlates with immune cell infiltration. It decreases chemotherapy sensitivity by regulating the MAPK14-HSP27 axis and inhibits the cytotoxic T-cell response by reducing ERAP1 stability and antigen processing. A biodegradable nanocarrier was developed for co-delivery of iRhom1 pre-siRNA and chemotherapy drugs, which effectively targets tumors through enhanced permeability and retention effect and CD44-mediated transcytosis. Inhibition of iRhom1 further enhances tumor targeting and uptake. Co-delivery of pre-siRhom and chemotherapy leads to enhanced antitumor efficacy and activated tumor immune microenvironment in multiple cancer models. Targeting iRhom1 together with chemotherapy could represent a strategy to overcome chemo-immune resistance in cancer treatment. The study also shows that iRhom1 negatively regulates antigen presentation and antitumor immune response by affecting ERAP1 stability and function. The PCL-CP nanocarrier efficiently targets tumors through CD44-mediated transcytosis and shows favorable pharmacokinetics. Inhibition of iRhom1 further improves CD44-dependent tumor targeting by decreasing CD44 cleavage. Co-delivery of pre-siRhom and chemotherapy leads to improved antitumor efficacy and enhanced antitumor immunity. The study highlights the potential of targeting iRhom1 in combination with chemotherapy to overcome chemo-immune resistance in cancer treatment.This study investigates the role of iRhom1 in chemoresistance and antitumor immunity, and develops a nanocarrier for co-delivering iRhom1 pre-siRNA and chemotherapy drugs to improve cancer treatment. iRhom1 is involved in cancer cell proliferation and negatively correlates with immune cell infiltration. It decreases chemotherapy sensitivity by regulating the MAPK14-HSP27 axis and inhibits the cytotoxic T-cell response by reducing ERAP1 stability and antigen processing. A biodegradable nanocarrier was developed for co-delivery of iRhom1 pre-siRNA and chemotherapy drugs, which effectively targets tumors through enhanced permeability and retention effect and CD44-mediated transcytosis. Inhibition of iRhom1 further enhances tumor targeting and uptake. Co-delivery of pre-siRhom and chemotherapy leads to enhanced antitumor efficacy and activated tumor immune microenvironment in multiple cancer models. Targeting iRhom1 together with chemotherapy could represent a strategy to overcome chemo-immune resistance in cancer treatment. The study also shows that iRhom1 negatively regulates antigen presentation and antitumor immune response by affecting ERAP1 stability and function. The PCL-CP nanocarrier efficiently targets tumors through CD44-mediated transcytosis and shows favorable pharmacokinetics. Inhibition of iRhom1 further improves CD44-dependent tumor targeting by decreasing CD44 cleavage. Co-delivery of pre-siRhom and chemotherapy leads to improved antitumor efficacy and enhanced antitumor immunity. The study highlights the potential of targeting iRhom1 in combination with chemotherapy to overcome chemo-immune resistance in cancer treatment.