RESUMO
The cytoskeleton facilitates tumor cells invasion into the bloodstream via vasculogenic mimicry (VM) for "attack", and protects cells against external threats through cytoskeletal remodeling and tunneling nanotubes (TNTs) for "defense". However, the existing strategies involving cytoskeleton are not sufficient to eliminate tumor metastasis due to mitochondrial energy supply, both within tumor cells and from outside microenvironment. Here, considering the close relationship between cytoskeleton and mitochondria both in location and function, we construct a nano-platform that combats the "attack" and "defense" of cytoskeleton in the cascading metastasis. The nano-platform is composed of KFCsk@LIP and KTMito@LIP for the cytoskeletal collapse and mitochondrial dysfunction. KFCsk@LIP prevents the initiation and circulation of cascading tumor metastasis, but arouses limited suppression in tumor cell proliferation. KTMito@LIP impairs mitochondria to trigger apoptosis and impede energy supply both from inside and outside, leading to an amplified effect for metastasis suppression. Further mechanisms studies reveal that the formation of VM and TNTs are seriously obstructed. Both in situ and circulating tumor cells are disabled. Subsequently, the broken metastasis cascade results in a remarkable anti-metastasis effect. Collectively, based on the nano-platform, the cytoskeletal collapse with synchronous mitochondrial dysfunction provides a potential therapeutic strategy for cascading tumor metastasis suppression.
Assuntos
Doenças Mitocondriais , Neovascularização Patológica , Humanos , Neovascularização Patológica/tratamento farmacológico , Linhagem Celular Tumoral , Citoesqueleto/patologia , Movimento CelularRESUMO
Post-surgical efferocytosis of tumor associated macrophages (TAMs) originates an immunosuppressive tumor microenvironment and facilitates abscopal metastasis of residual tumor cells. Currently, few strategies could inhibit efferocytosis while recovering the tumor-eliminative phagocytosis of TAMs. Herein, we developed an in situ hydrogel that contains anti-CD47 antibody (aCD47) and apocynin (APO), an inhibitor of nicotinamide adenine dinucleotide phosphate oxidase. This hydrogel amplifies the non-efferocytic phagocytosis of TAMs by (1) blocking the extracellular "Don't eat me" signal of efferocytosis with aCD47, which enhances the receptor-mediated recognition and engulfment of tumor cells by TAMs in the post-surgical tumor bed, and (2) by utilizing APO to dispose of tumor debris in a non-efferocytic manner, which prevents acidification and maturation of efferosomes and allows for M1-polarization of TAMs, leading to improved antigen presentation ability. With the complementary intervention of extracellular and intracellular, this hydrogel reverses the immunosuppressive effects of efferocytosis, and induces a potent M1-associated Th1 immune response against tumor recurrence. In addition, the in situ detachment and distal colonization of metastatic tumor cells were efficiently restrained due to the intervention of efferocytosis. Collectively, the hydrogel potentiates surgery treatment of tumor by recovering the tumor-elimination ability of post-surgical TAMs.