We developed a novel treatment strategy for metastatic cancer by synergizing photothermal therapy (PTT), chemotherapy, and immunotherapy through a nanosystem to trigger host antitumor immunity. The nanosystem was constructed by loading mitoxantrone (MTX), a chemotherapeutic agent, and SB-431542 (SB), a transforming growth factor beta (TGF-β) inhibitor, onto reduced graphene oxide (rGO). Intratumoral administration of rGO/MTX/SB, followed by non-invasive irradiation of a near-infrared laser, destroyed local primary tumors and inhibited distant metastases in 4T1 mouse mammary tumor model, which is poorly immunogenic and highly metastatic. After treatment, 70% of the tumor-bearing mice became long-term survivors and developed a tumor type-specific immunity to resist rechallenged tumor cells. We found that rGO-based PTT provided an immunogenic antigen source, forming in situ vaccination with rGO as an immune-adjuvant. The use of SB changed the tumor microenvironment and improved the therapeutic effect of MTX-generated chemotherapy and rGO-based PTT. The immunological functions of MTX, SB, and rGO acted synergistically to induce an effective tumor vaccination, as evidenced by the increased infiltration of tumor-specific cytotoxic CD8⁺ T lymphocytes and decreased infiltration of regulatory T cells (Tregs) in distal tumors. Collectively, we demonstrated that rGO/MTX/SB combined with laser irradiation provided a synergistic chemo-immuno-photothermal effect against tumors by in situ vaccination and inhibition of immunosuppressive microenvironment. This unique combination embodies a promising approach to treat metastatic cancers by inducing a systemic antitumor response through a local intervention.

我们开发了一种新的转移性癌症治疗策略，通过纳米系统协同光热疗法 (PTT)、化学疗法和免疫疗法来触发宿主抗肿瘤免疫。该纳米系统是通过将化学治疗剂米托蒽醌 (MTX) 和转化生长因子 β (TGF-β) 抑制剂 SB-431542 (SB) 加载到还原氧化石墨烯 (rGO) 上来构建的。在 4T1 小鼠乳腺肿瘤模型中，rGO/MTX/SB 的肿瘤内给药，然后是近红外激光的非侵入性照射，破坏了局部原发肿瘤并抑制了远处转移，该模型具有较差的免疫原性和高度转移性。治疗后，70% 的荷瘤小鼠成为长期存活者，并产生了肿瘤类型特异性免疫来抵抗再次攻击的肿瘤细胞。用 rGO 作为免疫佐剂进行原位接种。SB 的使用改变了肿瘤微环境并提高了 MTX 产生的化疗和基于 rGO 的 PTT 的治疗效果。MTX、SB 和 rGO 的免疫功能协同作用以诱导有效的肿瘤疫苗接种，如肿瘤特异性细胞毒性 CD8 ⁺ T 淋巴细胞浸润增加和远端肿瘤中调节性 T 细胞 (Treg) 浸润减少所证明。总的来说，我们证明了 rGO/MTX/SB 与激光照射相结合，通过原位提供了针对肿瘤的协同化学免疫光热效应。免疫抑制微环境的疫苗接种和抑制。这种独特的组合体现了一种通过局部干预诱导全身抗肿瘤反应来治疗转移性癌症的有前途的方法。