Patients with cancer often confront the decision of whether to continue high-dose chemotherapy at the expense of cumulative toxicities. Reducing the dose of chemotherapy regimens while preserving efficacy is sorely needed to preserve the performance status of these vulnerable patients, yet has not been prioritized. Here, we introduce a dual pronged approach to modulate the microenvironment of desmoplastic pancreatic tumors and enable significant dose deescalation of the FDA-approved chemotherapeutic nanoliposomal irinotecan (nal-IRI) without compromising tumor control. We demonstrate that light-based photodynamic priming (PDP) coupled with vitamin D3 receptor (VDR) activation within fibroblasts increases intratumoral nal-IRI accumulation and suppresses protumorigenic CXCL12/CXCR7 crosstalk. Combined photodynamic and biochemical modulation of the tumor microenvironment enables a 75% dose reduction of nal-IRI while maintaining treatment efficacy, resulting in improved tolerability. Modifying the disease landscape to increase the susceptibility of cancer, via preferentially modulating fibroblasts, represents a promising and relatively underexplored strategy to enable dose deescalation. The approach presented here, using a combination of three clinically available therapies with nonoverlapping toxicities, can be rapidly translated with minimal modification to treatment workflow, and challenges the notion that significant improvements in chemotherapy efficacy can only be achieved at the expense of increased toxicity.

中文翻译：

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维生素 D 受体激活和光动力启动使持久的低剂量化疗成为可能

癌症患者经常面临是否要以累积毒性为代价继续高剂量化疗的决定。非常需要在保持疗效的同时减少化疗方案的剂量，以保持这些脆弱患者的体能状态，但尚未得到优先考虑。在这里，我们介绍了一种双管齐下的方法来调节促纤维增生性胰腺肿瘤的微环境，并使 FDA 批准的化疗纳米脂质体伊立替康 (nal-IRI) 的剂量显着降低，而不会影响肿瘤控制。我们证明基于光的光动力启动 (PDP) 与成纤维细胞内的维生素 D3 受体 (VDR) 激活相结合，增加了瘤内 nal-IRI 的积累并抑制了促肿瘤的 CXCL12/CXCR7 串扰。肿瘤微环境的光动力和生化调节相结合，可将 nal-IRI 的剂量减少 75%，同时保持治疗效果，从而提高耐受性。通过优先调节成纤维细胞来改变疾病状况以增加癌症的易感性，代表了一种有希望且相对未开发的策略，以实现剂量降级。此处介绍的方法结合使用三种临床上可用的具有非重叠毒性的疗法，只需对治疗工作流程进行最少的修改即可快速转化，并挑战了化疗疗效的显着提高只能以增加毒性为代价的观念。从而提高耐受性。通过优先调节成纤维细胞来改变疾病状况以增加癌症的易感性，代表了一种有希望且相对未开发的策略，以实现剂量降级。此处介绍的方法结合使用三种临床上可用的具有非重叠毒性的疗法，只需对治疗工作流程进行最少的修改即可快速转化，并挑战了化疗疗效的显着提高只能以增加毒性为代价的观念。从而提高耐受性。通过优先调节成纤维细胞来改变疾病状况以增加癌症的易感性，代表了一种有希望且相对未开发的策略，以实现剂量降级。此处介绍的方法结合使用三种临床上可用的具有非重叠毒性的疗法，只需对治疗工作流程进行最少的修改即可快速转化，并挑战了化疗疗效的显着提高只能以增加毒性为代价的观念。