LC3-associated phagocytosis of neutrophils triggers tumor ferroptotic cell death in glioblastoma.

Necrosis in solid tumors is commonly associated with poor prognostic but how these lesions expand remains unclear. Studies have found that neutrophils associate with and contribute to necrosis development in glioblastoma by inducing tumor cell ferroptosis through transferring myeloperoxidase-containing granules. However, the mechanism of neutrophilic granule transfer remains elusive. We performed an unbiased small molecule screen and found that statins inhibit neutrophil-induced tumor cell death by blocking the neutrophilic granule transfer. Further, we identified a novel process wherein neutrophils are engulfed by tumor cells before releasing myeloperoxidase-containing contents into tumor cells. This neutrophil engulfment is initiated by integrin-mediated adhesion, and further mediated by LC3-associated phagocytosis (LAP), which can be blocked by inhibiting the Vps34-UVRAG-RUBCN-containing PI3K complex. Myeloperoxidase inhibition or Vps34 depletion resulted in reduced necrosis formation and prolonged mouse survival in an orthotopic glioblastoma mouse model. Thus, our study unveils a critical role for LAP-mediated neutrophil internalization in facilitating the transfer of neutrophilic granules, which in turn triggers tumor cell death and necrosis expansion. Targeting this process holds promise for improving glioblastoma prognosis. Synopsis: Neutrophils induce ferroptosis in glioblastoma, thus promoting necrosis during early tumor progression but the underlying mechanisms remain unclear. Here, neutrophil engulfment by tumor cells is uncovered as a critical step facilitating the transfer of neutrophilic granules and tumor cell ferroptosis. Statins inhibit neutrophil-induced tumor cell death by blocking neutrophilic granule transfer. Integrin-mediated cell adhesion is required for tumor cell killing by neutrophils. Neutrophils are engulfed by tumor cells before releasing myeloperoxidase-containing contents into tumor cells. LC3-associated phagocytosis is responsible for neutrophil internalization by tumor cells. Myeloperoxidase inhibition or Vps34 depletion reduces necrosis in glioblastomas and prolongs survival of tumor-bearing mice. Neutrophil engulfment by tumor cells facilitates transfer of neutrophilic granules and ferroptosis in brain cancer. [ABSTRACT FROM AUTHOR]