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We engineered mesothelin\u2010targeted CAR T cells to express heparanase (HPSE) fused to the truncated hepatitis A virus pX domain (pX\u2010\u03941\u201030), enabling surface display of HPSE on extracellular vesicles for localized, pH\u2010dependent ECM degradation within the acidic tumour microenvironment while limiting systemic exposure. HPSE\u2010pX\u2010\u03941\u201030 CAR T (referred to as HPSE CAR T) cells penetrated ECM mimics nearly fourfold more effectively than standard CAR T cells. They also expressed more TNF\u2010related apoptosis\u2010inducing ligand (TRAIL), Fas ligand (FasL), and perforin, leading to stronger tumour killing in 2D and 3D colorectal cancer models. HPSE\u2010pX\u2010\u03941\u201030 CAR T\u2013derived extracellular vesicles (EVs) retained CAR and chemokine receptors (CCR5\/CCR7), carried apoptotic ligands, and were efficiently taken up by tumour cells and T cells. EV exposure promoted T cell proliferation, CCR5 expression, and central\/stem\u2010like memory formation while lowering PD\u20101 and CD57. In HCT116 xenografts, HPSE CAR T cells showed increased intratumoral infiltration, and EVs from these cells promoted infiltration of host T cells. Treatment reduced tumour burden, extended survival beyond 70 days, and did not cause systemic toxicity. These results highlight a dual strategy of ECM remodelling and immune modulation, offering a translational approach to overcome barriers to CAR T therapy in colorectal cancer.<\/jats:p>","DOI":"10.1002\/jev2.70310","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T17:46:43Z","timestamp":1781200003000},"source":"Crossref","is-referenced-by-count":5,"title":["Heparanase\u2010Loaded CAR T Extracellular Vesicles Remodel the Colorectal Tumour Microenvironment and Boost T Cell Antitumor Immunity"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0000-2332","authenticated-orcid":false,"given":"Songshan","family":"Zhu","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, The First Dongguan Affiliated Hospital, School of Medical Technology Guangdong Medical University  Dongguan People's Republic of China"},{"name":"Dongguan Key Laboratory of Molecular Immunology and Cell Therapy Guangdong Medical University  Dongguan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Yin","sequence":"additional","affiliation":[{"name":"Institute of Transplant Medicine, The Second Affiliated Hospital of Guangxi Medical University, Guangxi Clinical Research Center for Organ Transplantation. 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