Toll 样受体 (TLR) 激动剂因其强大的免疫刺激特性而被开发为抗癌疗法。然而，测试 TLR 激动剂作为单一疗法的临床试验往往未能证明其对护理标准的显着改善。我们假设 TLR 激动剂免疫疗法的抗癌功效可以通过组合方法得到提高。为了防止全身联合疗法中常见的毒性增加，我们开发了一种水凝胶，可在癌症减灭手术期间局部提供低剂量的 TLR 激动剂组合。使用 WEHI 164 和双侧 M3-9-M 肉瘤和 CT26 结肠癌的肿瘤模型，我们评估了 Poly(I:C)、R848 和 CpG 两两组合在控制局部和远处肿瘤生长方面的功效。我们发现，TLR3 激动剂 Poly(I:C) 和 TLR7/8 激动剂 R848 的组合可驱动针对局部和远处肿瘤的抗肿瘤免疫。此外，局部聚(I:C)和R848的组合使肿瘤对全身免疫检查点阻断敏感，从而改善肿瘤控制。从机制上讲，我们证明了聚（I：C）和R848的局部治疗在抗肿瘤反应的早期将炎性单核细胞募集到肿瘤引流淋巴结。最后，我们提供了通过手术适用的可生物降解水凝胶在术中同时输送聚 (I:C) 和 R848 的概念证明。© 2024 作者。经泰勒许可出版

Toll-like receptor (TLR) agonists are being developed as anti-cancer therapeutics due to their potent immunostimulatory properties. However, clinical trials testing TLR agonists as monotherapy have often failed to demonstrate significant improvement over standard of care. We hypothesized that the anti-cancer efficacy of TLR agonist immunotherapy could be improved by combinatorial approaches. To prevent increased toxicity, often seen with systemic combination therapies, we developed a hydrogel to deliver TLR agonist combinations at low doses, locally, during cancer debulking surgery. Using tumor models of WEHI 164 and bilateral M3-9-M sarcoma and CT26 colon carcinoma, we assessed the efficacy of pairwise combinations of poly(I:C), R848, and CpG in controlling local and distant tumor growth. We show that combination of the TLR3 agonist poly(I:C) and TLR7/8 agonist R848 drives anti-tumor immunity against local and distant tumors. In addition, combination of local poly(I:C) and R848 sensitized tumors to systemic immune checkpoint blockade, improving tumor control. Mechanistically, we demonstrate that local therapy with poly(I:C) and R848 recruits inflammatory monocytes to the tumor draining lymph nodes early in the anti-tumor response. Finally, we provide proof of concept for intraoperative delivery of poly(I:C) and R848 together via a surgically applicable biodegradable hydrogel.© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.