Efferocytosis Nanoinhibitors to Promote Secondary Necrosis and Potentiate the Immunogenicity of Conventional Cancer Therapies for Improved Therapeutic Benefits

Abstract

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.

Improving combination cancer immunotherapy by manipulating dual immunomodulatory signals with enzyme-triggered, cell-penetrating peptide-mediated biomodulators

“…This observation clearly demonstrates a significant shift in macrophage polarization from M2- to M1-type. Although a prior study has shown that phosphatidylserine promotes tumor immunosuppression by inducing M2 polarization, 40 the observed macrophage polarization toward the M1-type in our study may be attributed to the combined exposure of phosphatidylserine and calreticulin, which can activate antitumor immunity. Regulatory T cells (Treg) are crucial for maintaining immune homeostasis and preventing autoimmune diseases, often limiting T cell-mediated antitumor immune responses during cancer immunotherapy.…”

Efferocytosis by macrophages in physiological and pathological conditions: regulatory pathways and molecular mechanisms

“…First, the factors determining macrophage turnover and lifespan during efferocytosis are incompletely understood. These efferocytosis-related phagocytes activate apoptosis and necrosis in neighboring cells, in addition to extensive efferocytosis ( 206 ). However, the mechanisms and features of these biological processes require further study.…”

Development of Granzyme B-targeted Smart Positron Emission Tomography Probes for Monitoring Tumor Early Response to Immunotherapy

“…Cancer is a major disease that threatens human life and health worldwide. − At present, cancer treatments mainly include surgery, chemotherapy, radiotherapy, and immunotherapy. − In the past decade, immunotherapy has made much progress in clinic and become the research focus, which utilizes the activated immune cells to kill tumor cells. − On the whole, however, the clinical objective response rate is lower than 30% due to the huge difference between individual patients and tumor types. In addition, immunotherapy is often accompanied by severe immune-related adverse reactions, including allergic reactions, inflammatory reactions, and even death in severe cases. − Therefore, it is necessary to screen possible responders and avoid unresponsive patients from ineffective treatment, which can reduce unnecessary side effects and provide opportunities for alternative treatment strategies …”