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The Tumor Microenvironment

The Tumor Microenvironment

Every normal cell or tissue is embedded in a complex local environment called stroma, consisting of different cell types, a basal membrane, and blood vessels. As normal cells mutate and develop into cancer cells, their local environment also changes to allow cancer progression. The tumor microenvironment (TME) consists of a complex cellular matrix of stromal cells and the developing tumor. The cross-talk between cancer cells and surrounding stromal cells is critical to disrupt normal tissue...

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Related Experiment Video

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Generation of Lymphocytic Microparticles and Detection of their Proapoptotic Effect on Airway Epithelial Cells

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Tumor Cell-Derived Microparticles Induced by Methotrexate Reprogram Neutrophil Antitumor Response via Lysosomal

Pingwei Xu¹, Xiaojie Zhang², Kai Chen³

¹The Department of Obstetrics, The First Affiliate Hospital of Wenzhou Medical University, Wenzhou, China.

Molecular Cancer Research : MCR

|December 15, 2025

Summary

Methotrexate-packaged microparticles activate neutrophils to release tumor-killing particles. This approach enhances CD8+ T cell responses, improving survival in lung cancer models and offering a new immunotherapy strategy.

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Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo

Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo

Published on: July 20, 2019

Area of Science:

Immunology
Oncology
Cell Biology

Background:

Neutrophils are key immune cells in the tumor microenvironment, influencing immunosuppression and impacting immunotherapy outcomes.
Current strategies for activating innate immune responses against tumors remain limited.

Purpose of the Study:

To investigate how methotrexate-packaged tumor cell-derived microparticles (MTX-MP) activate neutrophils for anti-tumor responses.
To elucidate the molecular mechanisms underlying MTX-MP-mediated neutrophil activation.

Main Methods:

Utilized methotrexate-packaged tumor cell-derived microparticles (MTX-MP) to activate neutrophils.
Investigated mitochondrial-lysosomal membrane contacts, NADH translocation, and reactive oxygen species (ROS) generation.
Assessed CD8+ T cell infiltration and anti-tumor responses.
Evaluated therapeutic efficacy using a combination of MTX-MP-activated neutrophils and CD8+ T cells in a Lewis lung carcinoma model.

Main Results:

MTX-MP activated neutrophils to release tumor-cytotoxic microparticles.
Observed increased tumor-infiltrated CD8+ T cells and enhanced CD8+ T cell anti-tumor activity.
Discovered that mitochondrial-lysosomal contacts facilitate NADH transfer, leading to lysosomal ROS production and calcium efflux, triggering neutrophil degranulation.
Combination therapy improved long-term survival rates in a Lewis lung carcinoma model.

Conclusions:

MTX-MP activate neutrophils to release microparticles that kill tumor cells.
This mechanism involves ROS generation and calcium signaling within neutrophils.
Activated neutrophils and CD8+ T cells represent a promising combinatorial therapeutic strategy for tumor immunotherapy.