Multimodal therapy is often used in oncology to overcome dosing limitations and chemoresistance. Recently, combination immunoradiotherapy has shown great promise in a select subset of patients with colorectal cancer (CRC). Furthermore, molecularly targeted agents delivered in tandem with immunotherapy regimens have been suggested to improve treatment outcomes and expand the population of responding patients. In this study, radiation-sensitizing small molecules niraparib (PARP inhibitor) and HS-173 (PI3K inhibitor) are identified as a novel combination that synergistically enhance toxicity and induce immunogenic cell death both in vitro and in vivo in a CRC model. These inhibitors were co-encapsulated in a polymer micelle to overcome solubility limitations while minimizing off-target toxicity. Mice bearing syngeneic colorectal tumors (CT26) were administered these therapeutic micelles in combination with X-ray irradiation and anti-CTLA-4 immunotherapy. This combination led to enhanced efficacy demonstrated by improved tumor control and increased tumor infiltrating lymphocytes. This report represents the first investigation of DNA damage repair inhibition combined with radiation to potentiate anti-CTLA-4 immunotherapy in a CRC model.

多峰疗法通常在肿瘤学中用于克服剂量限制和化学耐药性。最近，联合免疫放射疗法在结直肠癌（CRC）的部分患者中显示了巨大的希望。此外，已经提出了与免疫治疗方案一起递送的分子靶向药物可以改善治疗效果并扩大反应患者的人群。在这项研究中，辐射敏感的小分子尼拉帕利布（PARP抑制剂）和HS-173（PI3K抑制剂）被确定为在体外和体内协同增强毒性并诱导免疫原性细胞死亡的新型组合。在CRC模型中。将这些抑制剂共包封在聚合物胶束中，以克服溶解度限制，同时将脱靶毒性降至最低。将这些治疗性胶束与X射线辐射和抗CTLA-4免疫疗法相结合，给予患有同系结直肠癌（CT26）的小鼠。这种组合通过改善的肿瘤控制和增加的肿瘤浸润淋巴细胞而显示出增强的功效。该报告代表了对DNA损伤修复抑制联合放射线以增强CRC模型中抗CTLA-4免疫疗法的首次研究。