Strategies and challenges in promoting chimeric antigen receptor T cells trafficking and infiltration of solid tumors

Sep 24, 2026

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Chimeric antigen receptor T (CAR-T) therapy has shown strong success in hematologic malignancies, driving interest in extending its activity to solid tumors. Solid tumor biology differs markedly from blood-like tumor environments, requiring CAR-T cells to overcome a hostile tumor microenvironment to achieve effective contact with tumor cells. Abnormal angiogenesis, disrupted chemokine signaling, dense extracellular matrix, and stromal barriers limit CAR-T trafficking and infiltration. This review synthesizes strategies including vascular normalization, chemokine modulation, targeting physical barriers, combination treatments, and innovative delivery methods to enhance solid-tumor infiltration and improve therapeutic efficacy.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages10

Reading Time25 min

AccessFree to download

Introduction

CAR-T therapy for hematologic malignancies and rationale for solid tumors

Solid tumor barriers to CAR-T trafficking and infiltration

Strategies to enhance CAR-T infiltration in solid tumors

Vascular normalization

Chemokine production modulation

Targeting physical barriers and stromal components

Combination therapeutic approaches

Innovative cell delivery methods

Clinical developments and ongoing trials

Review Article Strategies and challenges in promoting chimeric antigen receptor T cells trafficking and infiltration of solid tumors Shibo Wang1,2,3, Xinyu Du1,2, Shen Zhao1,2, Yongzhan Nie1,2 1State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Xi’an, Shaanxi 710032, China; 2National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, Shaanxi 710032, China; 3Department of Emergency Intensive Care Unit, The 904th Hospital of PLA, Wuxi, Jiangsu 214044, China. Abstract The success of chimeric antigen receptor T (CAR-T) cells therapy for hematologic malignancies has sparked interest in potential applications for solid tumors. However, unlike the homogeneous, dynamic, and nutrient-rich hematologic environment, CAR-T cells must overcome the complex tumor microenvironment. Ensuring efficient contact with tumor cells remains a primary challenge to enhance the efficacy of CAR-T cell therapy. Abnormal tumor angiogenesis, disordered chemokine production, dense extracellular matrix, and stromal cells all act as biological barriers that hinder contact of CAR-T cells with tumor cells. This review summarizes specific strategies to promote vascular normalization, modulate chemokine production, target physical barriers, combine different therapeutic approaches, and innovative cell delivery methods to enhance infiltration of CAR-T cells into solid tumors. These strategies will help to overcome current limitations and enhance the effectiveness of CAR-T cell therapy for solid tumors. Keywords: Chimeric antigen receptor T-cell therapy; Solid tumors; Immunotherapy; Tumor infiltration; Chemokine production Introduction Immunotherapies (immune checkpoint inhibitors, adoptive T-cell therapy, and tumor vaccines) have rapidly developed in recent years as promising approaches to enhance the protective elimination of malignant tumor cells. [1] The tumor-killing effects of chimeric antigen receptor T (CAR-T) cells therapy involve recognition of specific antigens expressed on tumor cell membranes. Once activated, CAR-T cells can proliferate in the body, which usually requires only “one shot” to exert a therapeutic effect. [2] Currently, six CAR-T products targeting the B-cell antigen CD19 and B-cell maturation antigen are available for the treatment of acute B-lymphoblastic leukemia, diffuse large B-cell lymphoma, and multiple myeloma. [3–5] Tisagenlecleucel, an anti-CD19 chimeric antigen receptor cell, has demonstrated durable efficacy with a favorable safety profile over an extended follow-up of 29 months for patients with relapsed/refractory follicular lymphoma enrolled in the ELARA trial (NCT03568461) . The estimated 24-month rates of progression-free survival, response duration, overall survival, complete response, and overall response were 57.4%(95% confidence interval [CI]: 46 .2–67.0%),66 .4%(54 .3– 76.0%), 87.7% (78.3–93.2%), 68.1% (57.7–77.3%), | Access this article online | | | --- | --- | | Quick Response Code: | Website:
[www.cmj.org](www.cmj.org) | | | DOI:
10.1097/CM9.0000000000003803 | and 86.2%(77.5–92.4%), respectively. No new adverse effects or treatment-related deaths were reported.[6] CAR-T therapy achieved a durable therapeutic response in some patients, thereby offering a change to the treatment landscape for hematological cancers. [7] Also, CAR-T therapy, owing to its capability to continuously self-replicate, shows promise for the treatment of autoimmune diseases. [8] The success of CAR-T therapy for hematological cancers has directed subsequent research into applications for other solid tumors that currently lack effective treatments. Diffuse high-grade glioma is a refractory cancer that responds poorly to surgical resection, focal radiotherapy, and chemotherapy. [9] An early case report observed that local delivery of interleukin (IL)-13Rα2-targeted CAR-T cells achieved complete remission

FAQs

Why is promoting CAR-T cell trafficking and infiltration a key challenge in solid tumors?

Solid tumors create a complex microenvironment that prevents efficient CAR-T contact with tumor cells. Biological barriers such as abnormal angiogenesis, disordered chemokine production, dense extracellular matrix, and stromal cells hinder trafficking and infiltration.

What strategies does the review summarize to enhance CAR-T infiltration into solid tumors?

The review summarizes strategies to promote vascular normalization, modulate chemokine production, target physical barriers, combine different therapeutic approaches, and use innovative cell delivery methods.

How does the article position CAR-T therapy for solid tumors compared with hematologic cancers?

It notes that CAR-T success in hematologic malignancies has motivated broader research for solid tumors that currently lack effective treatments, but solid tumors require overcoming tumor microenvironment-related constraints to improve efficacy.

Sep 24, 2026

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