Modulating efferocytosis in the intestinal epithelial cells during colorectal cancer.

Colorectal cancer (CRC) is the thirdmost common cancer and a leading cause of cancer deaths worldwide, with over 1.9 million cases diagnosed in 2022. Due to poor response to classical cancer treatments, CRC is associated with low survival rates. This creates an urgent need for better understanding of CRC pathology. Cell death occurs continuously in solid tumors, and is also induced acutely, during chemotherapy. Dead cells are cleared by phagocytes via 'efferocytosis', an anti-inflammatory process that can lead to immune escape and reduced therapeutic efficacy. We hypothesized that efferocytosis might contribute to tumor development and that manipulating this process could be beneficial for CRC therapy. Here, we asked whether known approaches to enhance efferocytosis may alter disease parameters in experimental and genetic CRC mouse models. In the first approach, we chose transgenic expression of a chimeric efferocytosis receptor (BELMOTg) that removes dying cells in an anti-inflammatory manner, and in the second, we chose deleting a chloride transporter (Slc12a2KO) that increases efferocytosis but in a pro-inflammatory fashion. Despite detectable expression of the transgenic proteins, many parameters of CRC including CRC pathogenesis were not significantly altered in mice with BELMO overexpression or Slc12a2 knockout in the intestinal epithelial cells. This suggests that these two approaches to clearing apoptotic cells is not sufficient to alter CRC progression. Targeting other phagocytic cell types or using other models of CRC might reveal a role (or otherwise) for efferocytosis in mitigating CRC in the future.