CSF1R is a receptor tyrosine kinase that functions as a critical regulator of myeloid cell development and function 1. The receptor binds CSF1 and IL34 ligands, triggering autophosphorylation and activation of multiple downstream signaling cascades including PI3K/AKT, ERK1/2, and JNK pathways 1. CSF1R is primarily expressed in tissue-resident macrophages, osteoclasts, and microglia, where it controls cell survival, proliferation, and differentiation 1. In the tumor microenvironment, CSF1R-activated macrophages acquire pro-tumoral phenotypes, releasing inflammatory mediators that support tumor growth 2. CSF1R mutations cause CSF1R-associated microgliopathy (CAMP), a severe adult-onset leukoencephalopathy characterized by progressive neurodegeneration 3. Clinically, CSF1R inhibitors show therapeutic potential across multiple diseases: anti-CSF1R antibody axatilimab achieved 74% overall response in chr5 graft-versus-host disease patients 4, while CSF1R inhibitors are FDA-approved for tenosynovial giant cell tumors and under investigation for cancer immunotherapy 15. Notably, microglia replacement through bone marrow transplantation in CAMP patients halted disease progression over 24 months 3. Engineering inhibitor-resistant CSF1R variants enables safer microglia replacement strategies without systemic toxicity 6.