转移是与肿瘤相关的死亡率的主要贡献者。化疗和免疫疗法经常用于转移性实体瘤的治疗。然而,这些治疗方式与严重的不良反应和预防转移的效果有限有关.这里,我们报告了一种新的治疗策略,称为饥饿-免疫疗法,其中免疫检查点抑制剂与超长效L-天冬酰胺酶组合,所述超长效L-天冬酰胺酶是包含L-天冬酰胺酶(ASNase)和弹性蛋白样多肽(ELP)的融合蛋白,称为ASNase-ELP。ASNase-ELP的热敏感性使其能够在肿瘤内注射后产生原位储库,产生增加的剂量耐受性,改善药代动力学,持续释放,优化的生物分布,与游离ASNase相比,肿瘤保留增加。因此,在口腔癌的鼠模型中,黑色素瘤,还有宫颈癌,通过选择性和可持续地消耗肿瘤细胞存活所必需的L-天冬酰胺,ASNase-ELP的抗肿瘤功效明显优于ASNase或顺铂,一线抗实体瘤药物,没有任何可观察到的不利影响。此外,在阻止黑色素瘤转移方面,ASNase-ELP和免疫检查点抑制剂的组合比任一单独治疗更有效.总的来说,饥饿-免疫疗法的协同策略在重塑难治性转移性肿瘤的治疗前景和为下一代肿瘤治疗提供新的替代方案方面具有极好的前景.
Metastasis stands as the primary contributor to mortality associated with tumors. Chemotherapy and immunotherapy are frequently utilized in the management of metastatic solid tumors. Nevertheless, these therapeutic modalities are linked to serious adverse effects and limited effectiveness in preventing metastasis. Here, we report a novel therapeutic strategy named starvation-immunotherapy, wherein an immune checkpoint inhibitor is combined with an ultra-long-acting L-asparaginase that is a fusion protein comprising L-asparaginase (ASNase) and an elastin-like polypeptide (ELP), termed ASNase-ELP. ASNase-ELP\'s thermosensitivity enables it to generate an in-situ depot following an intratumoral injection, yielding increased dose tolerance, improved pharmacokinetics, sustained release, optimized biodistribution, and augmented tumor retention compared to free ASNase. As a result, in murine models of oral cancer, melanoma, and cervical cancer, the antitumor efficacy of ASNase-ELP by selectively and sustainably depleting L-asparagine essential for tumor cell survival was substantially superior to that of ASNase or Cisplatin, a first-line anti-solid tumor medicine, without any observable adverse effects. Furthermore, the combination of ASNase-ELP and an immune checkpoint inhibitor was more effective than either therapy alone in impeding melanoma metastasis. Overall, the synergistic strategy of starvation-immunotherapy holds excellent promise in reshaping the therapeutic landscape of refractory metastatic tumors and offering a new alternative for next-generation oncology treatments.