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Abstract Acetylation of extracellular proteins has been observed in many independent studies where particular attention has been given to the dynamic change of the microenvironmental protein post‐translational modifications. While extracellular proteins can be acetylated within the cells prior to their micro‐environmental distribution, their deacetylation in a tumor microenvironment remains elusive. Here it is described that multiple acetyl‐vWA domain‐carrying proteins including integrin β3 (ITGB3) and collagen 6A (COL6A) are deacetylated by Sirtuin family member SIRT2 in extracellular space. SIRT2 is secreted by macrophages following toll‐like receptor (TLR) family member TLR4 or TLR2 activation. TLR‐activated SIRT2 undergoes autophagosome translocation. TNF receptor associated factor 6 (TRAF6)‐mediated autophagy flux in response to TLR2/4 activation can then pump SIRT2 into the microenvironment to function as extracellular SIRT2 (eSIRT2). In the extracellular space, eSIRT2 deacetylates ITGB3 on aK416 involved in cell attachment and migration, leading to a promotion of cancer cell metastasis. In lung cancer patients, significantly increased serum eSIRT2 level correlates with dramatically decreased ITGB3‐K416 acetylation in cancer cells. Thus, the extracellular space is a subcellular organelle‐like arena where eSIRT2 promotes cancer cell metastasis via catalyzing extracellular protein deacetylation.