Gastric cancer is a worldwide health problem. Chemotherapy and radiotherapy are of great importance in the management of advanced gastric cancer. However, their therapeutic efficacy is limited by off-target side effects. Peptide-drug conjugates (PDCs) are a novel strategy for tumor-targeted drug delivery to overcome the existing drug resistance mechanisms and improve antitumor effects. Kita-Kyushu lung cancer antigen 1 (KK-LC-1) is exclusively expressed in several types of cancer including gastric cancer, representing a promising target for drug delivery. Here, we suggested KK-LC-1 as a potential target for PDC design for the first time and reported the first KK-LC-1-targeting PDC product 1131-MMAE, which is composed of a KK-LC-1-targeting peptide and an antimitotic drug conjugated by an enzymatically cleavable linker. We observed that 1131-MMAE could be efficiently endocytosed by KK-LC-1 positive gastric cancer cells for subsequent drug release and arrest the cell cycle at the most radiosensitive G2/M phase. We demonstrated that 1131-MMAE could significantly delay tumor growth with reduced toxicity than free drugs as a monotherapy. We further confirmed that 1131-MMAE was also a potent radiosensitizer. 1131-MMAE could selectively enhance the radiation response of KK-LC-1 positive tumor cells and achieve improved tumor control when combined with low-dose radiation. Overall, our study proposed an optimized therapeutic regimen for precision chemoradiotherapy, which has translational potential in multiple types of cancer.

胃癌是一个世界性的健康问题。化疗和放疗在晚期胃癌的治疗中具有重要意义。然而，它们的治疗效果受到脱靶副作用的限制。肽-药物偶联物（PDCs）是一种新的肿瘤靶向给药策略，可以克服现有的耐药机制，提高抗肿瘤效果。Kita-Kyushu 肺癌抗原 1 (KK-LC-1) 仅在包括胃癌在内的几种癌症中表达，代表了一种有希望的药物递送靶标。在这里，我们首次建议将 KK-LC-1 作为 PDC 设计的潜在目标，并报告了第一个 KK-LC-1 靶向 PDC 产品 1131-MMAE，它由 KK-LC-1 靶向肽组成以及由酶促切割接头结合的抗有丝分裂药物。我们观察到 1131-MMAE 可以被 KK-LC-1 阳性胃癌细胞有效内吞，用于随后的药物释放，并将细胞周期阻滞在对放射最敏感的 G2/M 期。我们证明了 1131-MMAE 作为单一疗法可以显着延缓肿瘤生长，同时降低毒性。我们进一步证实 1131-MMAE 也是一种有效的放射增敏剂。1131-MMAE与低剂量放射相结合，可选择性增强KK-LC-1阳性肿瘤细胞的放射反应，实现更好的肿瘤控制。总体而言，我们的研究提出了一种优化的精准放化疗治疗方案，该方案在多种癌症中具有转化潜力。