A sequential scheme including PTT and 2'3'-cGAMP/CQ-LP reveals the antitumor immune function of PTT through the type I interferon pathway

by Selleckchem | Nov 19 2023

Photothermal therapy (PTT) is a promising antitumor treatment that is easy to implement, minimally invasive, and precisely controllable, and evokes strong antitumor immunity. We believe that a thorough elucidation of its underlying antitumor immune mechanisms would contribute to the rational design of combination treatments with other antitumor strategies and consequently potentiate clinical use. In this study, PTT using indocyanine green (ICG) induced STING-dependent type I interferon (IFN) production in macrophages (RAW264.7 and bone marrow-derived macrophages (BMDMs)), as proven by the use of a STING inhibitor (C178), and triggered STING-independent type I IFN generation in tumor cells (CT26 and 4T1), which was inhibited by DNase pretreatment. A novel liposome coloaded with the STING agonist 2'3'-cGAMP (cGAMP) and chloroquine (CQ) was constructed to achieve synergistic effect with PTT, in which CQ increased cGAMP entrapment efficiency and prevented STING degradation after IFN signaling activation. The sequential combination treatment caused a significant increase in tumor cell apoptosis, probably due to interferon stimulating gene products 15 and 54 (ISG15 and ISG 54), and achieved a more striking antitumor inhibition effect in the CT26 tumor model than the 4T1 model, likely due to higher STAT1 expression and consequently more intense IFN signal transduction. In the tumor microenvironment, the combination treatment increased infiltrating CD8+T cells (4-fold) and M1-like TAMs (10-fold), and decreased M-MDSCs (over 2-fold) and M2-like TAMs (over 4-fold). Above all, in-depth exploration of the antitumor mechanism of PTT provides guidance for selecting sensitive tumor models and designing reasonable clinical schemes.

Comments:

The passage describes a study on Photothermal Therapy (PTT), a treatment for tumors that is minimally invasive and controllable, and its effects on the immune system. The study focuses on understanding the mechanisms behind PTT's antitumor effects and how it can be combined with other treatments for better outcomes.

**Summary of the Study:**

1. **PTT and Immune Response:**
   - PTT using indocyanine green (ICG) was employed, leading to STING-dependent type I interferon (IFN) production in macrophages and STING-independent type I IFN generation in tumor cells.
   - STING inhibitor (C178) was used to confirm STING-dependent IFN production in macrophages.
   - DNase pretreatment inhibited STING-independent IFN generation in tumor cells.

2. **Combination Treatment:**
- A novel liposome was developed, co-loaded with the STING agonist 2'3'-cGAMP (cGAMP) and chloroquine (CQ).
- CQ increased cGAMP entrapment efficiency and prevented STING degradation after IFN signaling activation.

3. **Antitumor Effects:**
- The combination treatment (PTT with cGAMP/CQ-loaded liposomes) led to increased tumor cell apoptosis, likely due to interferon stimulating gene products 15 and 54 (ISG15 and ISG 54).
- The treatment was more effective in the CT26 tumor model compared to the 4T1 model, possibly due to higher STAT1 expression and intense IFN signal transduction.

4. **Tumor Microenvironment Changes:**
- The combination treatment increased CD8+ T cells (4-fold) and M1-like tumor-associated macrophages (TAMs) (10-fold) in the tumor microenvironment.
- It decreased myeloid-derived suppressor cells (M-MDSCs) (over 2-fold) and M2-like TAMs (over 4-fold).

5. **Implications:**
- The study provides insights into the antitumor mechanisms of PTT, aiding in the selection of sensitive tumor models and the design of clinical treatment strategies.
- The findings suggest the potential of combining PTT with immunomodulatory agents for enhanced antitumor effects and immunogenicity.

In essence, the study demonstrates the effectiveness of combining PTT with a specific liposomal formulation containing cGAMP and CQ, leading to enhanced antitumor immune responses and providing valuable guidance for future clinical applications.