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 prometastatic 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.