Immunogenic Cell Death by the Novel Topoisomerase I Inhibitor TLC388 Enhances the Therapeutic Efficacy of Radiotherapy

SIMPLE SUMMARY: This study aims to evaluate the induction of immunogenic cell death (ICD) for anticancer immunity by the novel topoisomerase I inhibitor lipotecan. These results show that lipotecan can remarkably elicit ICD and increase tumor immunogenicity, which promotes the therapeutic efficacy of radiotherapy compared to conventional chemoradiotherapy in vivo. These results provide potential therapeutic strategies to improve the efficacy of chemoradiotherapy in colorectal cancer (CRC), which may increase the local control rate and decrease tumor relapse in locally advanced rectal cancer (LARC) patients who receive preoperative chemoradiotherapy. ABSTRACT: Rectal cancer accounts for 30–40% of colorectal cancer (CRC) and is the most common cancer-related death worldwide. The preoperative neoadjuvant chemoradiotherapy (neoCRT) regimen is the main therapeutic strategy for patients with locally advanced rectal cancer (LARC) to control tumor growth and reduce distant metastasis. However, 30–40% of patients achieve a partial response to neoCRT and suffer from unnecessary drug toxicity side effects and a risk of distant metastasis. In our study, we found that the novel topoisomerase I inhibitor lipotecan (TLC388) can elicit immunogenic cell death (ICD) to release damage-associated molecular patterns (DAMPs), including HMGB1, ANXA1, and CRT exposure. Lipotecan thereby increases cancer immunogenicity and triggers an antitumor immune response to attract immune cell infiltration within the tumor microenvironment (TME) in vitro and in vivo. Taken together, these results show that lipotecan can remodel the tumor microenvironment to provoke anticancer immune responses, which can provide potential clinical benefits to the therapeutic efficacy of neoCRT in LARC patients.