Related Experiment Video
Updated: Sep 1, 2025
Flow Cytometry-Based Isolation and Therapeutic Evaluation of Tumor-Infiltrating Lymphocytes in a Mouse Model of Pancreatic Cancer
Published on: January 17, 2025
Spatially targeting and regulating tumor-associated macrophages using a raspberry-like micellar system sensitizes
Ting Li1, Dong Chen1, Houqin Liu1
1Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Med-X Center for Materials, Sichuan University, Chengdu 610041, China. qinhe@scu.edu.cn.
Abstract:
Dense stroma and an immunosuppressive microenvironment severely hamper the antitumor therapeutic results of pancreatic cancer. Tumor-associated macrophages (TAMs) support the proliferation and invasion of tumor cells and contribute to the information of the immunosuppressive tumor microenvironment (TME). The repolarization of TAMs activates the antitumor immune response and sensitizes chemotherapy. Nevertheless, the difference in distributed mode between TAMs and tumor cells in tumor turns out to be an obstacle for dual targeting. To repolarize TAMs and elevate the chemoimmunotherapy outcome against pancreatic cancer, co-loading the TME responsive micellar system with gemcitabine (GEM) and PI3K inhibitor wortmannin (Wtmn) was used to dual target TAMs and tumor cells. GEM conjugated dendritic poly-lysine DGL (GD) nanoparticles were linked to polycaprolactone-polyethylene glycol micelles encapsulated with Wtmn (PP/Wtmn) via a cathepsin B (CTSB) substrate peptide to obtain raspberry-like GD@PP/Wtmn micelles. Upon arrival at the TME, GD was released in response to highly expressed CTSB, allowing deep penetration of the tumor and overcoming of the stromal barrier, while PP/Wtmn remained in the perivascular area where TAMs abundantly resided. By inhibiting the PI3K pathway, the M2-like TAMs were repolarized into M1-like TAMs and then activated antitumor immunity, further synergizing with GEM to suppress tumor growth. This tumor and TAMs dual targeting nanoplatform provides an alternative approach to sensitize chemoimmunotherapy against pancreatic cancer.
Insights
This study developed a dual-targeting nanoparticle system to deliver chemotherapy and a PI3K inhibitor, enhancing chemoimmunotherapy for pancreatic cancer by repolarizing tumor-associated macrophages (TAMs). The innovative nanoplatform overcomes stromal barriers and targets both tumor cells and TAMs for improved treatment outcomes.
Area of Science:
- Oncology
- Immunology
- Nanomedicine
Background:
- Pancreatic cancer is characterized by dense stroma and an immunosuppressive tumor microenvironment (TME) that limit therapeutic efficacy.
- Tumor-associated macrophages (TAMs) promote tumor progression and contribute to the immunosuppressive TME, hindering antitumor responses.
- Targeting both tumor cells and TAMs simultaneously is challenging due to their distinct distribution patterns within the tumor.
Purpose of the Study:
- To develop a novel nanoplatform for co-delivering gemcitabine (GEM) and a PI3K inhibitor (wortmannin, Wtmn) to simultaneously target pancreatic tumor cells and TAMs.
- To enhance chemoimmunotherapy outcomes by repolarizing TAMs and overcoming the immunosuppressive TME.
- To investigate the efficacy of a TME-responsive micellar system for dual targeting in pancreatic cancer treatment.
Main Methods:
- Constructed raspberry-like nanoparticles (GD@PP/Wtmn) by linking GEM-conjugated dendritic poly-lysine nanoparticles (GD) to Wtmn-encapsulated polycaprolactone-polyethylene glycol micelles (PP/Wtmn) via a cathepsin B (CTSB) substrate peptide.
- Engineered the nanoplatform for TME-responsive release of GD and preferential accumulation of PP/Wtmn in TAM-rich perivascular areas.
- Investigated the repolarization of M2-like TAMs to M1-like TAMs by PI3K pathway inhibition and assessed the subsequent activation of antitumor immunity and synergistic effects with GEM.
Main Results:
- The GD@PP/Wtmn micelles demonstrated TME-responsive release of GD upon encountering high CTSB levels, facilitating deep tumor penetration and overcoming stromal barriers.
- The PP/Wtmn component remained in perivascular regions, effectively targeting TAMs and repolarizing M2-like TAMs to M1-like TAMs via PI3K inhibition.
- The dual-targeting strategy synergized GEM chemotherapy with activated antitumor immunity, leading to significant suppression of pancreatic tumor growth.
Conclusions:
- The developed dual-targeting nanoplatform effectively repolarizes TAMs and enhances chemoimmunotherapy against pancreatic cancer.
- This approach offers a promising strategy to overcome the challenges posed by the dense stroma and immunosuppressive TME in pancreatic cancer.
- The TME-responsive micellar system provides an alternative and effective method for sensitizing chemoimmunotherapy in pancreatic cancer treatment.
