Activation of STING by the Novel Liposomal TLC388 Enhances the Therapeutic Response to Anti-PD-1 Antibodies in Combination with Radiotherapy

Abstract

Abstract Rectal cancer constitutes 30–40% of colorectal cancer (CRC) cases and is a major global cause of cancer-related mortality. The main therapeutic approach for locally advanced rectal cancer patients is chemoradiotherapy (CRT), which controls tumor growth and diminishes distant metastasis. Nevertheless, 30–40% of patients exhibit a partial response to CRT because of the detrimental effects of drug toxicity and because of the potential risk of delaying surgery. In our study, we discovered that the novel topoisomerase I inhibitor lipotecan (TLC388) can induce immunogenic cell death (ICD), leading to the release of damage-associated molecular patterns (DAMPs), including HMGB1, ANXA1, and CRT. Lipotecan enhances cancer immunogenicity, stimulating the antitumor immune response that promotes the infiltration of immune cells within the tumor microenvironment (TME), both in vitro and in vivo. Collectively, these findings highlight the capacity of lipotecan to reshape the tumor microenvironment, thereby stimulating anticancer immune responses, as well as holding promise for enhancing the therapeutic efficacy of neoadjuvant CRT in patients with local advanced rectal cancer.