Efferocytosis of apoptotic cancer cells by tumor-associated
macrophages
or other phagocytes is reported to promote tumor immunosuppression
by preventing them from secondary necrosis, which would lead to the
release of intracellular components and thus enhanced immunogenicity.
Therefore, current apoptosis-inducing cancer treatments (e.g., chemotherapy
and radiotherapy) are less satisfactory in eliciting antitumor immunity.
Herein, a nanoparticulate inhibitor of efferocytosis is prepared by
encapsulating BMS777607, a hydrophobic inhibitor of receptors in macrophages
responsible for phosphatidylserine-dependent efferocytosis, with biocompatible
poly(lactic-co-glycolic acid) and its amphiphilic
derivatives. The yielded nano-BMS can inhibit the efferocytosis of
apoptotic cancer cells, thus redirecting them to immunogenic secondary
necrosis. As a result, intratumorally injected nano-BMS is capable
of activating both innate and adaptive antitumor immunity to achieve
greatly improved therapeutic responses, when synergized with nonimmunogenic
chemotherapy by cisplatin, immunogenic chemotherapy by oxaliplatin,
or radiotherapy by external beams. Moreover, we further demonstrate
that the inhalation of nano-BMS could significantly promote the efficacy
of cisplatin chemotherapy to suppress tumor lung metastases. Therefore,
this study highlights a general strategy to potentiate the immunogenicity
of different cancer treatments by suppressing efferocytosis-propelled
tumor immunosuppression, showing tremendous clinical potential in
rescuing existing cancer therapies for more effective treatment.