Ferrocene,　known　for　its　＇sandwich＇　structure　and　Fenton　catalytic　activity　for　tumor　treatment,　its　two-dimensional　(2D)　self-assembly　has　not　yet　been　exploited　for　therapeutic　applications.　Perfluorocarbons　(PFCs)　can　carry　and　transport　oxygen　to　alleviate　tumor　hypoxia.　Nevertheless,　designing　ferrocene　derivatives　with　PFC　chains　to　alleviate　tumor　hypoxia　and　improve　cancer　treatment　remains　a　challenge.　Here,　we　first　synthesized　ferrocene　derivatives　with　different　PFC　chains　(nF-Fc,　n　=　5,　9,　13)　by　conjugating　perfluorocarbonic　acids　with　2-(ferrocenylethynyl)aniline　(Fc).　These　derivatives　were　able　to　self-assemble　into　2D　nanosheets,　with　hydrated　particle　size　decreasing　as　the　chain　length　increased.　The　chain　lengths　also　influenced　the　oxygen-carrying　capacity,　iron　release　capacity,　and　glutathione　consumption　capacity,　all　of　which　impacted　their　ability　to　alleviate　tumor　hypoxia,　produce　intracellular　reactive　oxygen　species,　and　enhance　chemodynamic　therapeutic　efficacy.　Notably,　PFC　incorporation　altered　the　mechanism　of　induced　cell　death.　By　elucidating　the　effects　of　ferrocene　derivatives　with　different　PFC　chains　on　the　hypoxic　tumor　microenvironment　(TME)　and　their　therapeutic　efficacy,　this　research　advances　the　development　of　ferrocene-based　2D　materials　for　cancer　treatment　and　offers　a　novel　approach　to　optimize　compound　structures　better　regulation　of　the　hypoxic　TME,　ultimately　improving　therapeutic　outcomes.　©　2025　Elsevier　Ltd