Department of Medical Ultrasound, Center of Minimally Invasive Treatment for Tumor, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, P.R. China.
Ultrasound Research and Education Institute, Clinical Research Center for Interventional Medicine, School of Medicine, Tongji University, Shanghai, P.R. China.
J Nanobiotechnology. 2024 Oct 30;22(1):667. doi: 10.1186/s12951-024-02871-0.
Preclinical studies demonstrating high cure rates with PD1/PD-L1 combinations have led to numerous clinical trials, but emerging results are disappointing. These combined immunotherapies are commonly employed for patients with refractory tumors following prior treatment with cytotoxic agents. Here, we uncovered that the post-chemotherapy tumor presents a unique mechanical microenvironment characterized by an altered extracellular matrix (ECM) elasticity and increased stiffness, which facilitate the development of aggressive tumor phenotypes and confer resistance to checkpoint blocking therapy. As thus, we rationally designed an in situ nanocomposite hydrogel system, LOS&FeOX@Gel, which enabled effective and specific delivery of the therapeutic payloads (losartan [LOS] and oxaliplatin [OX]) into tumor. We demonstrate that sustained release of LOS effectively remodels the tumor mechanical microenvironment (TMM) by reducing ECM deposition and its associated "solid stress", thereby augmenting the efficacy of OX and its immunological effects. Importantly, this hydrogel system greatly sensitized post-chemotherapy tumor to checkpoint blocking therapy, showing synergistic therapeutic effects against cancer metastasis. Our study provides mechanistic insights and preclinical rationale for modulating TMM as a potential neoadjuvant regimen for tumor to optimize the benefits of chemo-immunotherapy, which lays the groundwork for leveraging "mechanical-immunoengineering" strategies to combat refractory tumors.
临床前研究表明，PD1/PD-L1 联合治疗具有很高的治愈率，这导致了许多临床试验的开展，但新出现的结果令人失望。这些联合免疫疗法通常用于在细胞毒性药物治疗后出现难治性肿瘤的患者。在这里，我们发现化疗后的肿瘤呈现出一种独特的机械微环境，其特征是细胞外基质（ECM）弹性改变和硬度增加，这有利于侵袭性肿瘤表型的发展，并赋予其对检查点阻断治疗的抗性。因此，我们合理设计了一种原位纳米复合水凝胶系统 LOS&FeOX@Gel，该系统能够将治疗有效载荷（氯沙坦[LOS]和奥沙利铂[OX]）有效且特异性地递送到肿瘤部位。我们证明，LOS 的持续释放通过减少 ECM 的沉积及其相关的“固形压力”来有效重塑肿瘤的机械微环境（TMM），从而增强 OX 的疗效及其免疫作用。重要的是，这种水凝胶系统极大地增强了化疗后肿瘤对检查点阻断治疗的敏感性，显示出对癌症转移的协同治疗效果。我们的研究为调节 TMM 提供了机制上的见解和临床前依据，将其作为肿瘤的潜在新辅助治疗方案，以优化化疗免疫治疗的益处，为利用“机械免疫工程”策略对抗难治性肿瘤奠定了基础。
