Cancer　associated　fibroblasts　(CAFs)　are　crucial　stromal　cells　in　desmoplastic　triple-negative　breast　cancer　(TNBC)　inducing　abundant　extracellular　matrix　(ECM),　resulting　in　the　poor　penetration　of　therapeutic　drugs　and　immunosuppressive　tumor　microenvironment　(TME).　Here,　a　safe　and　green　nanoregulator　ORM　based　on　oleanolic　acid　(OA)　nanogel　incorporating　sonosensitizer　rose　bengal　(RB)　and　photothermal　agent　methylene　blue　(MB)　with　three-pronged　deep　intratumoral　penetration　and　TME　modulation　was　fabricated　to　improve　therapies　of　TNBC.　The　inactivation　of　CAFs　by　deformable　OA　nanogel　allows　ORM　enter　into　cancer　cells　more　easily.　The　following　light　irradiation　not　only　decomoposes　MB　to　exert　photothermal　therapy　(PTT)　to　degrade　collagen　and　remodel　the　ECM　for　improved　penetration,　but　also　triggers　the　RB　release.　Finally,　the　ultrasound　further　promotes　the　deep　penetration　of　RB　to　achieve　sonodynamic　therapy　(SDT).　ORM　with　programmable　PTT　and　SDT　reshapes　tumor　immune　microenvironment　and　boosts　anti-PD-L1-mediated　immunotherapy,　leading　to　remarkable　inhibition　of　the　growth　of　primary　and　distant　tumors　and　protection　against　tumor　rechallenge.　The　present　three-pronged　penetration　and　programmable　regulation　approach　by　a　nanoregulator　composed　of　clinically-applied　agents　provide　a　promising　pathway　to　design　clinically　transformable　nanomedicine　for　effective　combination　therapy　of　TNBC.　©　2022　Elsevier　B.V.