Research Projects

Cancer continues to claim millions of lives worldwide and remains one of the most lethal and challenging diseases of our time. Despite advances, the standard treatment for many solid tumors still relies heavily on systemic chemotherapy. Among the options, platinum (Pt)-based drugs such as cisplatin, carboplatin, and oxaliplatin have remained a mainstay in clinical oncology for decades, used widely across ovarian, colorectal, non-small cell lung, head and neck, testicular, and bladder cancers. These agents primarily exert their anticancer effect through DNA-adduct formation, leading to replication arrest and apoptosis. Despite their success, the initial response is often transient due to the rapid development of resistance, driven largely by DNA damage repair (DDR) mechanisms. The formation of DNA adducts by platinum compounds triggers multiple DDR pathways. Notably, tumors with BRCA1/2 mutations (termed BRCAness) exhibit heightened sensitivity to platinum-based therapies. This has expanded the relevance of DDR-targeted therapies beyond traditional indications. The combination of platinum-based drugs with DDR inhibitors (DDRi), particularly PARPi such as olaparib, has demonstrated strong potential in inducing synthetic lethality, selectively eliminating tumor cells while minimizing damage to healthy tissues. In parallel, cancer immunotherapy has advanced considerably, with immune checkpoint blockade (ICB) therapies and other immunomodulatory approaches transforming treatment options for several malignancies. Despite this progress, ovarian and colorectal cancers largely remain immunologically “cold” tumors, marked by poor T-cell infiltration and limited responsiveness to ICB monotherapy. Recent studies have shown that certain chemotherapeutics, particularly oxaliplatin, possess the distinctive capability to induce immunogenic cell death (ICD). These ICD-specific markers activate dendritic cells and prime cytotoxic T-cell responses, contributing to the downstream elimination of cancer cells through immune-mediated mechanisms. On the other hand, DDRis, including PARPi treatment, has also been shown to lead to the accumulation of cytosolic double-stranded DNA, which subsequently activates the cyclic GMP-AMP synthetase-stimulator of interferon genes (cGAS-STING) pathway. This immunogenic signaling cascade results in the upregulation of interferon-stimulated genes, enhancing dendritic cell (DC) antigen-presenting capacity and promoting a CD8+ T cell-mediated antitumor immune response. While combination strategies involving oxaliplatin, DDRis, and ICBs hold considerable promise, clinical success has been limited. The failure of single-agent therapies and even free-drug combinations is frequently attributed to differences in pharmacokinetics, biodistribution, off-target toxicity, and inconsistent drug exposure at the tumor site. In light of these challenges, a smart, self-immolative, tumor-specific prodrug platform offers a promising strategy to achieve controlled and traceless release of active drugs at the tumor site or within tumor cells. This dual-action strategy is designed to selectively enhance DNA damage and apoptosis in cancer cells, while simultaneously inducing ICD and activating the cGAS–STING pathway. The resulting immune stimulation promotes innate immune activation and supports T-cell infiltration, converting traditionally non-immunogenic (“cold”) tumors into immunologically active ones. To further improve tumor specificity and therapeutic efficacy, this prodrug approach will be extended onto a nanoparticle-based delivery platform. This enables both passive and active targeting for preferential tumor accumulation, while allowing the co-loading of combination agents either through covalent attachment using self-immolative linkers or via non-covalent encapsulation. The nanoparticle matrix also offers protection for labile components and facilitates stimulus-responsive release in the tumor microenvironment.