Background　An　increasing　number　of　studies　have　demonstrated　that　CX3CL1　is　involved　in　the　development　of　tumors　and　may　thus　be　considered　a　new　potential　therapeutic　target　for　them.　However,　the　function　of　CX3CL1　in　clear　cell　renal　cell　carcinoma　(ccRCC)　remains　poorly　defined.　Methods　The　pan-cancer　expression　pattern　and　prognostic　value　of　CX3CL1　were　evaluated　in　this　study.　Moreover,　the　relationship　of　CX3CL1　expression　with　the　tumor　microenvironment,　especially　the　tumor　immune　microenvironment,　was　analyzed.　Our　analyses　employed　public　repository　data.　Additionally,　we　generated　stable　CX3CL1-overexpressing　786-O　cells　to　determine　the　role　of　CX3CL1　in　vitro　via　cell　viability　and　transwell　assays.　A　xenograft　tumor　model　was　used　to　determine　the　role　of　CX3CL1　in　vivo.　The　association　between　CX3CL1　and　ferroptosis　sensitivity　of　tumor　cells　was　assessed　using　Ferrostatin-1.　Results　Our　findings　indicated　the　involvement　of　CX3CL1　in　the　occurrence　and　development　of　ccRCC　by　acting　as　a　tumor　suppressor.　We　also　found　that　ccRCC　patients　with　high　CX3CL1　expression　showed　better　clinical　outcomes　than　those　with　low　CX3CL1　expression.　The　findings　of　our　epigenetic　study　suggested　that　the　expression　of　CX3CL1　in　ccRCC　is　correlated　with　its　DNA　methylation　level.　Furthermore,　the　CX3CL1　expression　level　was　closely　related　to　the　infiltration　level　of　CD8(+)　T　cells　into　the　tumor　microenvironment　(TME).　CX3CL1　showed　different　predictive　values　in　different　immunotherapy　cohorts.　Finally,　CX3CL1　overexpression　inhibited　tumor　cell　proliferation　and　metastasis　and　promoted　tumor　ferroptosis　sensitivity　in　ccRCC.　Conclusions　This　study　revealed　the　role　of　CX3CL1　as　a　tumor　suppressor　in　ccRCC.　Our　findings　indicated　that　CX3CL1　plays　a　crucial　role　in　regulating　the　ccRCC　TME　and　is　a　potential　predictor　of　immunotherapy　outcomes　in　ccRCC.　We　also　found　that　CX3CL1　can　promote　ferroptosis　sensitivity　in　ccRCC　cells.