Functional pH-Responsive Nanoparticles for Immune Reprogramming in MSS Colorectal Cancer via ER Stress-Induced...

Area of Science:

• Oncology
• Nanotechnology
• Immunotherapy

Background:

• Microsatellite-stable colorectal cancer (MSS CRC) exhibits resistance to immune checkpoint inhibitors (ICIs) due to immune evasion, tumor-associated macrophage (TAM) enrichment, and a suppressive tumor microenvironment (TME).
• Existing therapies struggle to overcome immune exclusion in MSS CRC, necessitating novel strategies to reprogram the TME and enhance anti-tumor immune responses.

Purpose of the Study:

• To engineer a pH-responsive solid lipid nanoparticle (SLN) system for co-delivery of CB-5083 (VCP/p97 inhibitor), miR-142 (PD-L1 inhibitor), and imiquimod (TLR7 agonist).
• To achieve spatially confined induction of endoplasmic reticulum stress (ERS) and immune reprogramming within the TME of MSS CRC.
• To develop a clinically translatable strategy for chemo-immunotherapy in immune-refractory tumors.

Main Methods:

• SLNs were coated with PEG-PGA for pH-triggered de-shielding and functionalized with targeting peptides (PD-L1, EGFR, ER-homing).
• The nanoplatform was designed for selective tumor uptake, TAM targeting, and subcellular ER localization.
• Combination therapy (CB-5083 + miR-142 + imiquimod) was evaluated in CT-26 bearing mice models.

Main Results:

• The nanoplatform demonstrated acid-triggered de-shielding, selective uptake by CRC and TAMs, and ER localization.
• CB-5083 induced apoptosis and autophagy via ERS signaling pathways; miR-142 suppressed PD-L1 and EMT markers; imiquimod promoted dendritic cell maturation and M1 polarization.
• Combined therapy significantly suppressed tumor growth, reduced immunosuppressive cytokines, increased CD4+/CD8+ T cell infiltration, decreased Tregs and M2-TAMs, induced immunogenic cell death, and conferred resistance to tumor rechallenge.

Conclusions:

• The developed TME-responsive nanoplatform effectively integrates ERS induction, checkpoint modulation, and cytokine suppression to overcome immune exclusion in MSS CRC.
• This strategy reprograms the TME into a T cell-permissive state, offering a promising approach for chemo-immunotherapy in immune-refractory tumors.
• The nanoplatform exhibited tumor-preferential accumulation, minimal off-target exposure, and low systemic toxicity, indicating clinical translatability.