Cancer immunotherapy, particularly immune checkpoint inhibitors (ICIs), has significantly improved treatment outcomes for multiple types of cancer.

However, only a subset of patients respond effectively to these therapies.

One major limitation is insufficient tumour immunogenicity, as tumour cells can evade immune surveillance by downregulating major histocompatibility complex class I (MHC-I) molecules or suppressing antigen presentation pathways.

Meanwhile, platinum-based chemotherapy, a classical cancer treatment modality, can induce tumour cell death through DNA damage and partially stimulate anti-tumour immune responses.

However, its application in combination immunotherapy is restricted by nonspecific distribution and the systemic toxicity associated with high-dose administration.

Therefore, how to effectively enhance tumour immunogenicity while minimising toxicity and achieving synergy with ICIs has become a critical challenge in the field of metal-based therapeutics.

Recently, a research team led by Zijian Guo and Jie Li from the School of Chemistry and Chemical Engineering at Nanjing University published a study entitled Uncoupling tumour immunogenicity from cell death with platinum(IV)-antibody conjugates in National Science Review.

The study presents a new strategy based on platinum(IV)-antibody conjugates (Pt-ADCs), in which antibody-mediated targeted delivery confines the “metal immune effect” of platinum drugs to tumours, thereby mechanistically uncoupling tumour immunogenicity activation from high-dose cytotoxicity.

Building upon their previous work in platinum drug development and antibody chemical modification, the researchers employed a site-specific glycoengineering strategy to achieve homogeneous antibody modification and precise control of the drug-to-antibody ratio (DAR), thereby constructing structurally defined Pt-ADC systems.

Unlike conventional antibody-drug conjugates that rely on external cleavable linkers, this platform takes advantage of the coordination chemistry of platinum by introducing kinetically stable platinum(IV) prodrugs that simultaneously function as both linkers and drug precursors.

Within the reductive tumour microenvironment, the platinum(IV) complexes are gradually reduced to release active platinum(II) species, enabling controlled drug release without requiring additional linker structures.

Functional studies demonstrated that the low-dose platinum delivered by Pt-ADCs was insufficient to induce substantial tumour cell death directly, but effectively upregulated MHC-I expression, enhanced antigen processing and presentation, and activated immune-related signalling pathways.

As a result, tumour cells remained in a sustained immune-recognisable state.

In syngeneic tumour models, this strategy significantly promoted the expansion of tumour-reactive T-cell receptor (TCR) clonotypes and showed strong synergy with anti-PD-1 therapy, enhancing CD8-positive T-cell-mediated anti-tumour immune responses and achieving tumour suppression superior to either monotherapy or simple combination treatment.

In addition, ICP-MS quantitative analysis demonstrated that Pt-ADCs substantially reduced platinum exposure in non-tumour tissues, thereby alleviating systemic toxicity.

Further kinetic studies revealed that rational design of the axial ligands enabled tunable and stepwise reductive release of platinum(IV) payloads within the tumour microenvironment.

The optimised system maintained good serum stability while allowing mild and sustained platinum release, thereby maintaining low but persistent platinum levels within tumours over extended periods.

This release pattern helped sustain MHC-I upregulation and immune activation while avoiding the cytotoxic or immunosuppressive effects associated with transient high platinum concentrations, ultimately establishing an adjustable functional balance between “immune activation” and “cytotoxicity.”

Overall, this study proposes a new platinum-based therapeutic strategy characterised by “low toxicity but high immunogenicity.” By constructing structurally defined Pt-ADCs, the researchers achieved low-dose tumour-targeted platinum delivery and controlled release, effectively enhancing tumour immunogenicity without relying on strong cytotoxic effects, while significantly improving the efficacy of immune checkpoint blockade therapy.

This work not only provides a chemical and biological foundation for the precise regulation of “metal immune effects,” but also opens new avenues for the application of platinum drugs in precision cancer immunotherapy.

Source: Science China Press