An Enhanced Cancer Immunogenic Cell Death Strategy: Fibrate-Oxaliplatin(IV) Conjugates with Modulating Tumor Immune...

Area of Science:

• Oncology
• Medicinal Chemistry
• Immunology

Background:

• Current immunogenic cell death (ICD) strategies face challenges for clinical use, necessitating innovative approaches.
• Modulating the tumor microenvironment (TME) is crucial for enhancing cancer therapy efficacy.

Purpose of the Study:

• To design and synthesize novel oxaliplatin-like fibrate-derived platinum(IV) conjugates (2-7) for improved ICD induction.
• To investigate the potential of these conjugates in modulating the TME for enhanced antitumor effects.

Main Methods:

• Synthesis and characterization of platinum(IV) conjugates.
• In vitro cytotoxicity assays and mechanistic studies (DNA damage, mitochondrial dysfunction, ER stress).
• Evaluation of ICD markers, TME modulation (immune cell infiltration, cytokine secretion, immune checkpoint expression), and in vivo antitumor efficacy and toxicity.

Main Results:

• Conjugates accumulated in cells, releasing active components and exhibiting significant cytotoxicity, with compound 5 being 319-fold more potent than oxaliplatin.
• Mechanistic studies confirmed DNA damage, mitochondrial dysfunction, ER stress, and apoptosis induction, linked to a self-amplifying cycle with cholesterol metabolism.
• Enhanced ICD marker release, increased CD8+ T cell infiltration, elevated cytokine secretion, and reduced PD-L1/Treg immunosuppression were observed.
• In vivo studies demonstrated favorable biocompatibility, potent antitumor activity, and reduced toxicity compared to oxaliplatin.

Conclusions:

• The designed platinum(IV) conjugates effectively induce ICD and modulate the TME through a self-amplifying cycle involving cholesterol metabolism.
• These novel compounds represent a promising therapeutic strategy for cancer treatment with enhanced efficacy and safety.
• Further clinical investigation of these conjugates is warranted for their potential in cancer immunotherapy.