Cantharidin-Loaded Nanomedicine Modified with Amphiphilic Peptides Induce Immunogenic Cell Death to Enhance PD-1
Yang Tang1, Qun Jiang2, Rongli Chen3
1Department of Oncology, The Affiliated Traditional Chinese Medicine Hospital, Guangzhou Medical University, Guangzhou 510000, China.
Abstract:
Recent advances in immune checkpoint inhibitors (ICIs), particularly those targeting PD-1/PD-L1, have transformed cancer treatment. However, their efficacy is often hampered by the immunosuppressive tumor microenvironment (TME). Here, we developed a cantharidin-loaded nanomedicine (CA@TPGS-AmP), composed of D-α-tocopheryl polyethylene glycol succinate (TPGS) and naturally derived amphiphilic peptides (AmP), designed to enhance PD-1 blockade via induction of immunogenic cell death (ICD). In vitro, CA@TPGS-AmP markedly improved the solubility of cantharidin and exhibited superior penetration in 3D tumor spheroids. It effectively triggered key ICD events, including calreticulin (CRT) surface exposure, ATP release, and HMGB1 translocation, thereby promoting dendritic cell (DC) maturation. In vivo, CA@TPGS-AmP significantly augmented the antitumor efficacy of PD-1 therapy in 4T1 orthotopic breast cancer and LLC lung cancer models. Mechanistically, the combination therapy remodeled the TME into an immunostimulatory state by increasing CD8+ T cell infiltration and activation, leading to enhanced tumor suppression compared to monotherapies. These findings support CA@TPGS-AmP as a promising adjunct to PD-1 blockade and highlight the potential of natural product-based nanomedicine in advancing cancer immunotherapy.
Insights
This study introduces a novel cantharidin nanomedicine (CA@TPGS-AmP) that enhances PD-1 blockade cancer immunotherapy by inducing immunogenic cell death (ICD) and reprogramming the tumor microenvironment (TME). The combination therapy shows significant antitumor efficacy in preclinical models.
Area of Science:
- Oncology
- Immunology
- Nanomedicine
- Materials Science
Background:
- Immune checkpoint inhibitors (ICIs), especially PD-1/PD-L1 blockers, have revolutionized cancer treatment.
- The immunosuppressive tumor microenvironment (TME) limits the effectiveness of current immunotherapies.
- Novel strategies are needed to overcome TME-mediated resistance and improve therapeutic outcomes.
Purpose of the Study:
- To develop a cantharidin-loaded nanomedicine (CA@TPGS-AmP) to enhance PD-1 blockade therapy.
- To investigate the ability of CA@TPGS-AmP to induce immunogenic cell death (ICD) and modulate the TME.
- To evaluate the combined therapeutic efficacy of CA@TPGS-AmP and PD-1 blockade in preclinical cancer models.
Main Methods:
- Synthesis and characterization of CA@TPGS-AmP, a nanomedicine comprising D-α-tocopheryl polyethylene glycol succinate (TPGS) and amphiphilic peptides (AmP).
- In vitro assessment of cantharidin solubility, tumor spheroid penetration, and induction of ICD markers (CRT exposure, ATP release, HMGB1 translocation).
- In vivo evaluation of combination therapy efficacy in 4T1 breast cancer and LLC lung cancer models, analyzing immune cell infiltration and activation.
Main Results:
- CA@TPGS-AmP demonstrated improved cantharidin solubility and enhanced penetration in 3D tumor spheroids.
- The nanomedicine effectively induced key ICD events and promoted dendritic cell (DC) maturation in vitro.
- Combination therapy with CA@TPGS-AmP and PD-1 blockade significantly suppressed tumor growth in vivo.
- The treatment strategy remodeled the TME, increasing CD8+ T cell infiltration and activation.
Conclusions:
- CA@TPGS-AmP is a promising nanomedicine for enhancing PD-1 blockade immunotherapy.
- The developed nanomedicine effectively induces ICD and overcomes TME-mediated immunosuppression.
- Natural product-based nanomedicine holds significant potential for advancing cancer immunotherapy strategies.
