Our　previous　research　has　demonstrated　that　Arthrospira　phycocyanobilin　(PCB)　is　a　natural　anticancer　photosensitizer　(PS)　with　a　linear　tetrapyrrole　structure.　Natural　sources　of　PSs　are　harmless　to　the　human　body　and　exhibit　relatively　low　cytotoxicity　compared　to　clinical　PSs.　The　challenge　has　always　been　to　enhance　their　activity　while　maintaining　their　biocompatibility,　which　is　crucial　for　the　development　of　natural　anticancer　PSs.　This　study　shows　that　the　central　coordination　of　transition　metal　ion　Co2+　in　linear　tetrapyrroles　increases　the　quantum　yield　of　reactive　oxygen　species　(ROS)　and　improves　the　photodynamic　anticancer　activity　of　PCB　following　light　exposure.　The　ROS　quantum　yield　of　Co-PCB　is　0.5109,　which　is　2.45　times　higher　than　that　of　PCB　(0.1481).　Co-PCB　exhibited　approximately　4.48　times　the　photodynamic　anticancer　activity　of　PCB　on　HeLa　cells　(IC50:　10.69　±　0.50　μM　vs.　47.91　±　0.91　μM).　Zn-phthalocyanine　(ZnPc)　is　a　representative　second-generation　PS.　Co-PCB　exhibits　greater　biosafety,　while　its　anticancer　therapeutic　index　is　55.14　%　higher　than　that　of　ZnPc.　Co-PCB　has　the　potential　to　be　used　in　photodynamic　anticancer　therapy.　Furthermore,　it　could　be　used　as　a　basis　for　developing　and　applying　other　natural　linear　tetrapyrrole　compounds　to　improved　their　activity　while　maintaining　biocompatibility.　©　2025　Elsevier　Ltd