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© 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)., The decision whether endosomes enter the degradative or recycling pathway in mammalian cells is of fundamental importance for pathogen killing, and its malfunctioning has pathological consequences. We discovered that human p11 is a critical factor for this decision. The HscA protein present on the conidial surface of the human-pathogenic fungus Aspergillus fumigatus anchors p11 on conidia-containing phagosomes (PSs), excludes the PS maturation mediator Rab7, and triggers binding of exocytosis mediators Rab11 and Sec15. This reprogramming redirects PSs to the non-degradative pathway, allowing A. fumigatus to escape cells by outgrowth and expulsion as well as transfer of conidia between cells. The clinical relevance is supported by the identification of a single nucleotide polymorphism in the non-coding region of the S100A10 (p11) gene that affects mRNA and protein expression in response to A. fumigatus and is associated with protection against invasive pulmonary aspergillosis. These findings reveal the role of p11 in mediating fungal PS evasion., This work was funded by the Deutsche Forschungsgemeinschaft (DFG) cluster of excellence Balance of the Microverse (Project-ID 390713860, Gepris 2051), the DFG-ANR project “AfuInf (316898429),” DFG CRC/Transregio 124 “FungiNet” (A1, Z2; 210879364), DFG CRC 1278 “PolyTarget” (Z01; 316213987), Leibniz project (K217/2016), Fundação para a Ciência e a Tecnologia (FCT) (PTDC/MED-OUT/1112/2021, UIDB/50026/2020, UIDP/50026/2020, NORTE-01-0145-FEDER-000039), EU’s Horizon 2020 (847507), “la Caixa” Foundation (ID 100010434) and FCT (LCF/PR/HR17/52190003), Gilead Research Scholars Program - Anti-Fungals, and EU-funded Horizon 2020 project HDM-FUN (ID 847507). M.R. and F.S. were supported by the DFG excellence graduate school Jena School for Microbial Communication, and C.C. by FCT (CEECIND/04058/2018).