Overcoming physical stromal barriers to cancer immunotherapy
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Updated: Oct 25, 2025
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Published on: January 17, 2025
Seung Woo Chung1,2, Yunxuan Xie1,2,3, Jung Soo Suk4,5,6
1Center for Nanomedicine, The Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD, 602921231, USA.
Abstract:
Immunotherapy has emerged as an unprecedented hope for the treatment of notoriously refractory cancers. Numerous investigational drugs and immunotherapy-including combination regimens are under preclinical and clinical investigation. However, only a small patient subpopulation across different types of cancer responds to the therapy due to the presence of several mechanisms of resistance. There have been extensive efforts to overcome this limitation and to expand the patient population that could be benefited by this state-of-the-art therapeutic modality. Among various causes of the resistance, we here focus on physical stromal barriers that impede the access of immunotherapeutic drug molecules and/or native and engineered immune cells to cancer tissues and cells. Two primary stromal barriers that contribute to the resistance include aberrant tumor vasculatures and excessive extracellular matrix build-ups that restrict extravasation and infiltration, respectively, of molecular and cellular immunotherapeutic agents into tumor tissues. Here, we review the features of these barriers that limit the efficacy of immunotherapy and discuss recent advances that could potentially help immunotherapy overcome the barriers and improve therapeutic outcomes.
Insights
Immunotherapy shows promise for refractory cancers, but resistance limits patient benefit. This review focuses on physical stromal barriers, like abnormal tumor vasculature and dense extracellular matrix, hindering immune cell and drug delivery.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
- Drug Delivery
Background:
- Immunotherapy offers significant hope for treating refractory cancers, with many new drugs and combinations in development.
- However, a limited patient population responds to immunotherapy due to various resistance mechanisms.
- Physical stromal barriers within tumors are increasingly recognized as a major cause of immunotherapy resistance.
Purpose of the Study:
- To review the role of physical stromal barriers in limiting immunotherapy efficacy.
- To discuss how aberrant tumor vasculature and excessive extracellular matrix impede drug and immune cell infiltration.
- To explore recent advances aimed at overcoming these barriers to improve immunotherapy outcomes.
Main Methods:
- Literature review of preclinical and clinical studies on immunotherapy resistance.
- Analysis of the impact of tumor stroma, including vasculature and extracellular matrix, on therapeutic agent access.
- Synthesis of current research on strategies to overcome stromal barriers.
Main Results:
- Aberrant tumor vasculature restricts the extravasation of immunotherapeutic drugs and immune cells.
- Excessive extracellular matrix deposition hinders the infiltration of immune cells into tumor tissues.
- These physical barriers significantly limit the effectiveness of immunotherapy in a majority of cancer patients.
Conclusions:
- Physical stromal barriers, specifically abnormal tumor vasculature and dense extracellular matrix, are critical determinants of immunotherapy resistance.
- Overcoming these barriers is essential for expanding the patient population that can benefit from immunotherapy.
- Emerging strategies targeting stromal components hold promise for enhancing immunotherapy efficacy and improving clinical outcomes.
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