Spatially targeting of tumor-associated macrophages and cancer cells for suppression of spontaneously metastatic tumor

The interaction between cancer cells and M2 tumor-associated macrophages (M2-TAMs) facilitates tumor growth and metastasis. However, cancer cells and M2-TAMs have different spatial distribution patterns, which requires distinct drug delivery strategies. Herein, based on different tumor-penetrating ability of nanocarriers, we developed a combinatory strategy that consists of a TAMs-targeting liposome (alanine-alanine-asparagine (AAN)-Lip-regorafenib (Rego)) and a cancer cells-targeting copolymer (internalizing RGD modified with N-(2-hydroxypropyl) methacrylamide-doxorubicin (iRGD-HD)). Our study confirmed AAN-Lip-Rego accumulated at perivascular sites where M2-TAM is located, while iRGD-HD penetrated into deep site of tumor to enter cancer cells. Thereafter, we found iRGD-HD induced cancer cells undergoing immunogenic cell death to enhance tumor infiltration of CD8⁺ T cells. Meanwhile, AAN-Lip-Rego efficiently repolarized TAMs from M2 into M1 to alleviate tumor immunosuppression, thus reviving CD8⁺ T cells. Moreover, the repolarization of TAMs led to dramatic downregulation of pro-metastatic factors expressed on cancer cells. As a result, such combinatory approach elicited robust antitumor immune responses and generated considerable anti-tumor and anti-metastasis efficacy to markedly inhibit primary tumor and spontaneous lung metastasis.