SPP1 and neoplasm: By activating the colony stimulating factor 1 receptor (CSF1R) pathway in macrophages, tumor derived SPP1 can also increase the expression of programmed death ligand 1 (PD-L1) and cause macrophage reprogramming to M2 type through the integrin and protein tyrosine kinase 2 (PTK2)-Akt signaling pathways (41, 71).