Autophagy inhibition recovers deficient ICD-based cancer immunotherapy.

ICD effect is usually accompanied with robust autophagy that can depredate immune-associated antigens in tumors, thereby weakening the immune response against tumor growth. To circumvent this dilemma, we combined an ICD inducer (Shikonin, SHK) with an autophagy inhibitor (hydroxychloroquine, HCQ) for colon cancer immunotherapy. Notably, HCQ boosted SHK-induced antigen exposure in colon cancer in vitro and in vivo. However, autophagy inhibition caused loss of ATP, which compromised antitumor immune response. Therefore, a compensatory strategy was employed by introducing ATP as a remote loading gradient of the liposome to encapsulate HCQ (LipHCQa). LipHCQa achieved an excellent antitumor efficiency without dampening the immune response. Furthermore, a systematic determination of the optimal dosage of combined LipSHK and LipHCQa suggested that autophagy inhibiting at an appropriate dosage level was beneficial for maximizing ICD-based antitumor immunity. This study proved that autophagy inhibitors can recover the deficient ICD-based antitumor immune response and present potential clinical applications for cancer immunotherapy.