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  • Cationic Liposome-Encapsulated Adenoviruses: Overcoming CAR-Dependent Resistance & Systemic Antitumor Immunity

  • Elham Kamalkazemi,1 Fereydoon Abedi-Gaballu,2 Nasser Hashemi-Goralel,3 Babak Negahdari,4 Firozeh Safaeeyan,5 Effat Alizadeh,6,*
    1. Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
    2. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
    3. Cancer Gene Therapy Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
    4. Department of Medical Biotechnology, School of Advanced Science in Medicine, Tehran University of Medical Sciences, Tehran, Iran
    5. Department of Microbiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
    6. Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran


  • Introduction: Oncolytic virotherapy using recombinant adenoviruses represents a promising therapeutic approach for the treatment of various malignancies. However, the clinical efficacy of naked adenovirus is critically dependent on the expression level of the Coxsackievirus and Adenovirus Receptor (CAR) on target cells. Unfortunately, CAR downregulation is frequently observed in many human tumors, including colorectal, ovarian, pancreatic, and breast cancers, posing a major limitation to the successful application of adenovirus-based therapies. This review aims to explore the potential of encapsulating adenoviruses within cationic liposomes as a novel strategy to overcome CAR-dependent resistance and to potentiate systemic antitumor immune responses.
  • Methods: This article is based on a comprehensive review of the most recent preclinical studies published between 2021 and 2025. The analyzed studies' subjects include tumor models characterized by low CAR expression, in vivo evaluations of both local and abscopal (distant) effects, and detailed immunological assessments.
  • Results: The findings suggest that encapsulation of adenovirus in cationic liposomes, such as the DOTA02P-folate formulation, acts through three main mechanisms: first, enabling CAR receptor-independent entry through folate receptor-mediated endocytosis and direct membrane fusion that enables efficient transduction of CAR-negative cells; second, inducing a peritumoral response such that in bilateral tumor models, intratumoral administration of the liposomal formulation not only eradicates the injected tumor but also causes regression of the untreated tumor on the contralateral side, a response that is largely dependent on natural killer (NK) cells; and third, converting a cold tumor into a hot one by increasing the infiltration of cytotoxic T lymphocytes and releasing damage-associated molecular patterns (DAMPs) that render the tumor environment susceptible to subsequent immunotherapies.
  • Conclusion: Collectively, cationic liposome-encapsulated adenoviral vectors overcome CAR-dependent transduction barriers while simultaneously activating both innate and adaptive immunity. This platform offers a universal, cancer-type-independent strategy for oncolytic virotherapy and holds significant promise for the design of future clinical trials, particularly in patients with treatment-resistant malignancies.
  • Keywords: Cationic Liposome, Adenovirus, CAR-Dependent Resistance, Cancer

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