Supramolecular Combination Chemotherapy: Directly Inducing Immunogenic Cell Death To Inhibit Tumor Metastasis via Host-Guest Interactions

Tumor metastasis is a difficult clinical problem to solve due to tumor heterogeneity and the emergence of antiapoptotic clones driven by tumor evolution. Clinical combination chemotherapy remains a standard treatment for solid metastasis tumors but with worse treatment efficiency. It is worth exploring a high-efficiency and low-side-effect therapeutic method to solve solid metastases. Herein, we fabricate a supramolecular combination chemotherapeutic system based on host-guest interactions using a cucurbit[8]uril complex (CB[8]-lobaplatin-oxaliplatin, CLO). We explored whether CLO can induce colorectal cancer cell death by activating immunogenic cell death (ICD) to inhibit cancer cell migration in a safe and effective manner. CLO inhibits the viability of human colorectal cancer cells (HCT116) at only 10 μM and alleviates the cytotoxicity induced by lobaplatin-oxaliplatin (LO) in normal colorectal cells (NCM460). Interestingly, CLO can trigger ICD in colorectal tumor cells, and our results verified the upregulations of high mobility group box 1 (HMGB1) and adenosine triphosphate (ATP) release and cell surface calreticulin (CRT) exposure. Besides, we found that CLO can inhibit tumor migration both and , and bio-AFM characterization of tumor cellular surface also confirmed this phenomenon. To further investigate the underlying mechanisms of the antitumor effects of CLO, quantitative proteomics was employed, and the results indicated that the citrate cycle (TCA cycle), protein processing in the endoplasmic reticulum, cGMP-PKG signaling pathway, p53 signaling pathway, chemical carcinogenesis, and necroptosis signaling pathway might contribute to CLO-induced antitumor effects. Collectively, our study suggests that the supramolecular combination chemotherapeutic system based on CB[8] host-guest complex can activate ICD to inhibit metastasis in antitumor strategy and exhibits a remarkable potential for supramolecular immunotherapy.