Triphenyl　phosphate　(TPP),　a　wide-used　organophosphate　flame　retardants　(OPFRs),　is　suspected　to　be　a　risk　factor　for　the　female-specific　cancers,　but　underlying　toxicity　mechanisms　of　environmentally　relevant　dose　exposure　remain　unclear.　Herein,　a　strategy　of　spherical　covalent　organic　framework　(TPB-BPTP-COF)-assisted　laser　desorption　ionization　mass　spectrometry　(LDI-MS),　which　benefited　from　fast　analysis　speed,　facile　sample　preprocessing,　and　high　throughput,　was　proposed　for　unveiling　the　biomarkers　of　breast　cancer　(BC)　and　the　relationship　between　TPP　exposure　and　progression　of　BC　in　mice　by　serum　metabolism　analysis.　The　results　displayed　that　13　metabolites　associated　with　BC　development　were　up-regulated　in　experimental　group　versus　healthy　control　mice.　Moreover,　long-term　exposure　to　environmentally　relevant　doses　of　TPP　was　found　to　promote　BC,　mainly　by　affecting　glycolysis/gluconeogenesis,　pyrimidine　metabolism,　pantothenic　acid　and　CoA　biosynthesis,　and　β-alanine　metabolism.　This　work　proved　the　potential　application　of　COFs　as　LDI-MS　substrates　in　analyzing　complex　biological　samples,　and　also　revealed　the　risk　of　long-term　low-dose　exposure　to　TPP　in　the　development　of　BC.　©　2024　Elsevier　B.V.