化学免疫疗法,其中涉及同时使用化疗药物和免疫治疗药物以达到协同作用,在癌症治疗中起着至关重要的作用。然而,免疫抑制微环境,肿瘤特异性不足,和严重的全身副作用阻碍了它们的协同治疗作用和临床应用。在这里,T细胞和自然杀伤(NK)细胞,它们是最重要的免疫效应细胞,两者都被激活以逆转免疫抑制微环境。为了简化药物载体,选择奥沙利铂作为化疗药物,既能诱导ICD效应,又能激活T细胞。选择IL-15来激活NK细胞。为了提高载体的生产率并减少副作用,开发了易于制备的热敏水凝胶(OXL/IL-15TG),用于共负载奥沙利铂脂质体(OXL)和IL-15。结直肠癌,适合原位给药,被选为癌症模型。由此产生的新型三重连锁联合疗法可以直接杀死肿瘤细胞,诱导ICD效应并激活NK细胞。给药后,OXL/IL-15TG作为药物贮存库,无干扰地减缓OXL和IL-15的释放。OXL约165.47±7.04nm被动递送至肿瘤组织,杀伤肿瘤细胞和诱导ICD效应。结果证明IL-15刺激NK细胞的活化。在荷瘤小鼠模型中,OXL/IL-15TG表现出显著和值得注意的抗肿瘤功效,扩大生存率。值得注意的是,OXL/IL-15TG导致肿瘤组织内CD3+CD8+T细胞和CD3-CD49+NK细胞的浸润增强。总的来说,三联联合治疗为结直肠癌的治疗提供了新的思路。
Chemo-immunotherapy, which involves the simultaneous use of chemotherapy drug and immunotherapeutic agent to achieve synergistic effects, plays a crucial role in cancer treatment. However, the immunosuppressive microenvironment, insufficient tumor specificity, and serious systemic side effects hinder their synergistic therapeutic effects and clinical applications. Herein, T cell and natural killer (NK) cell, which are the most important immune effector cells, were both activated to reverse the immunosuppressive microenvironment. To simplify drug carriers, oxaliplatin was selected as the chemotherapy drug which can both induce the ICD effect and activate T cells. IL-15 was selected to activate NK cells. To enhance the productivity of the carrier and reduce side effects, the easy-prepared thermosensitive hydrogel (OXL/IL-15 TG) was developed to co-load oxaliplatin-loaded liposomes (OXL) and IL-15. Colorectal cancer, suitable for in situ administration, was selected as model cancer. The resulting novel triple-interlocked combination therapy could directly kill the tumor cells, induces ICD effect and activate NK cells. After administration, OXL/IL-15 TG was formed serving as a drug depot, slowing releasing OXL and IL-15 non-interferencely. OXL around 165.47±7.04 nm was passively delivered to tumor tissue, killing tumor cells and inducing ICD effect. The results demonstrated that IL-15 stimulated the activation of NK cells. In tumor-bearing mice models, OXL/IL-15 TG exhibited a remarkable and noteworthy anti-tumor efficacy, and expanded survival rate. Notably, OXL/IL-15 TG led to an enhanced infiltration of CD3+CD8+ T cells and CD3-CD49+ NK cells within the tumor tissue. Overall, the triple-interlocked combination therapy provided a new idea for colorectal cancer therapy.