**6.5 Cancer**

Although efferocytosis plays a vital role in tissue homeostasis, since clearance of apoptotic cells is followed by immunosuppressive responses, its role in cancer can be detrimental to the host. Indeed, tumour tissue is subject to high-speed cell proliferation and apoptosis, and the process of apoptotic cell clearance, which is associated with anti-inflammatory responses, can encourage tumour escape from immune surveillance and encourage tumour progression. Therefore, some studies have shown that different ligands and receptors involved in efferocytosis may be over-expressed in certain tumour cells and may cause tumorigenesis [40]. Soki et al. have shown that prostate cancer patients' tissue and serum exosomes have a higher degree of MFGE8 expression than controls and that efferocytosis caused by MFGE8 leads to macrophage polarisation towards an M2 phenotype that promotes tumour [33]. Furthermore, in human oral squamous cell carcinoma (SCC) surgical specimens, the immunohistochemical expression of MFGE8 has been associated with some clinical tumour characteristics, including size, stage and invasion patterns [34]. Intensified Mer TK signalling in tumour tissues has been associated with cancer development, metastasis, and resistance to care [35]. Some studies have also been carried out showing that inhibiting the activation of efferocytosis against cancer progression can be successful.

In the co-cultivation of prostatic cancer cells and macrophages, the use of antibodies against MFGE8 substantially decreased the conversion of macrophages to the tumor-promoting M2 phenotype [33]. Tumor production has been minimized in mice by monoclonal antibodies to MFGE8. Consequently, inhibiting efferocytosis and preventing the expression of anti-inflammatory interleukins will improve the immune system's efficacy and anti-tumor effects [99]. However, literature data on the impact of efferocytosis on cancer is troublesome, as there is also evidence that cancer progression may be promoted by a defective efferocytosis. For instance, cancer cells have been shown to express high levels of CD47 on their surface in order to escape from phagocytosis. Therefore, a new approach to cancer treatment, based on inhibiting the expression of CD47 by siRNA or monoclonal antibodies in tumour cells, has emerged to prevent the transduction of don't-eat-me signals into macrophages and increase the phagocytosis of cancer cells [48, 49]. A significant point on this controversial topic is linked to anti-cancer medications. These drugs cause the death of cancer cells by [150–152]. Anti-cancer drug-induced cancer cell apoptosis, accompanied by increased expression of anti-inflammatory cytokines (TGFβ, PGE2, PAF and IL-10), is triggered by efferocytosis in the tumour setting. As a result, this process will lead to the silent anti-tumour response of the immune system [50]. In addition, it has been shown that anthracyclines (e.g., doxorubicin) promote the expression of eat-me signals on the surface of tumour cells, leading to immunogenic cell death [5]. Additionally, as described, during the apoptotic process, apoptotic cells begin to release ATP and UTP within 2 to 4 hours. These nucleoside triphosphates have been demonstrated to act as chemo attractants and to inhibit inflammatory responses in the recruitment of macrophages [11]. The use of chemotherapy drugs to induce apoptosis in tumour cells can increase the

release of nucleoside triphosphates up to 100 times higher, with a significant effect on inflammatory inhibition and suppression of the immune system, although the amounts of nucleotides released during apoptosis are low, so that their effects on immune response suppression are limited. Therefore, a serious reconsideration of anti-cancer drugs is anticipated in the coming years, by fully understanding the function of these agents in apoptotic tumour cell efferocytosis [51, 52] and the related therapeutic consequences.
