Dual Cell Death Mechanism Enhances PD-L1 Checkpoint Therapy Effectiveness

A novel nanoplatform designed to simultaneously trigger two distinct forms of cell death has demonstrated the ability to enhance the effectiveness of anti-PD-L1 checkpoint therapy in cancers with low PD-L1 expression. The cuproptosis and disulfidptosis co-delivery targeted (Cadict) nanodrug exploits copper-sulfur coordination chemistry to co-deliver copper ions and cystine while integrating glucose oxidase to create conditions essential for disulfidptosis execution.

The dual cytotoxic mechanism triggers an immunogenic cell death-like phenotype and activates the integrated stress response, promoting PD-L1 upregulation through Eif5b-dependent translation. This synergy between redox-driven cytotoxicity and immune modulation potentiates anti-PD-L1 efficacy, leading to robust tumor regression and durable immunological memory.

Immune checkpoint blockade therapies have revolutionized cancer treatment by unleashing host immune responses to eradicate tumors. Central to this mechanism is the co-inhibitory interaction of programmed cell death protein 1 (PD-1) and its ligand PD-L1, which suppresses cytotoxic T lymphocyte activity, leading to their exhaustion and apoptosis and enabling immune evasion. Over 1000 clinical studies have demonstrated the therapeutic efficacy of PD-1/PD-L1 inhibitors, with approvals across multiple advanced malignancies like melanoma, non-small cell lung cancer, and microsatellite instable-high or mismatch repair-deficient colorectal cancer.

While PD-L1 blockade agents such as atezolizumab and avelumab have demonstrated remarkable clinical efficacy, a substantial proportion of patients with low PD-L1 expression fail to derive clinical benefit from these therapies. Emerging evidence suggests that PD-L1 upregulation may not only enhance chemotherapy responsiveness but also potentiate targeted degradation of PD-L1, implying that elevating PD-L1 expression could broaden the therapeutic window for immune checkpoint blockade.

Copper upregulates PD-L1 expression, thus facilitating tumor immune evasion. Cuproptosis-based nanomedicines have been shown to elevate tumor PD-L1 levels and synergize with anti-PD-L1 therapy to enhance antitumor responses. A copper-dependent form of regulated cell death facilitates immunogenic cell death while reprogramming the immunosuppressive tumor microenvironment to improve immune checkpoint blockade efficacy. However, intrinsic or acquired resistance to single-mode cell death often undermines the therapeutic benefit.

Disulfidptosis, a recently defined form of programmed cell death, is triggered by disulfide stress and NADPH depletion under glucose deprivation. This process manifests aberrant accumulation of disulfide bonds in actin cytoskeletal proteins, leading to structural collapse and cell death. While emerging evidence suggests that disulfidptosis and its associated genes regulate immune function, its role in shaping the tumor microenvironment and potential for therapeutic synergy in combination with other cell death pathways remains poorly understood.

The Cadict nanoplatform represents the first synthetic compound developed to concurrently induce cuproptosis and disulfidptosis. The epidermal growth factor receptor-targeted nanoplatform is designed to co-induce these two cell death mechanisms, thereby synergistically augmenting tumor cytotoxicity and sensitizing cancers to anti-PD-L1 therapy. The resulting synergy provides a new paradigm for overcoming immune checkpoint blockade resistance via targeted tumor sensitization.