Molecular Cancer | Advances in PD-L1-Targeted Radionuclide-Drug Conjugates for Lung Cancer Therapy

This study systematically summarizes the potential of PD-L1 as a target for radionuclide-drug conjugates (RDCs) in lung cancer, providing clear direction for developing dual-functional therapies that combine immune activation with precision radiotherapy. It offers direct reference value for designing novel PD-L1-targeted strategies.

 

Literature Overview

The article “Radionuclide-drug conjugates in lung cancer: advances in precision therapy and clinical translation,” published in the journal Molecular Cancer, systematically explores recent advances in radionuclide-drug conjugates (RDCs) for precision therapy in lung cancer. The study comprehensively reviews 66 RDC candidates, covering multidimensional optimization strategies from target selection and carrier design to radionuclide matching. It particularly emphasizes the roles of key molecules such as SSTR, FAP, EGFR, and PD-L1 in tumor targeting. The research further highlights that with the development of novel alpha-emitters and stable chelators, RDCs are transitioning from concept to clinical practice, showing particular promise in overcoming resistance to conventional radiotherapy.

Background Knowledge

Lung cancer remains the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for over 85% of cases. Although targeted therapies and immune checkpoint inhibitors (e.g., anti–PD-L1 antibodies) have significantly improved outcomes for some patients, primary or acquired resistance remains common. While PD-L1 expression is used as a biomarker for immunotherapy, its dynamic heterogeneity and immunosuppressive tumor microenvironment limit durable response rates. Moreover, although conventional radiotherapy can enhance antigen presentation, it may also trigger systemic immunosuppression. Therefore, achieving synergy between localized precision radiotherapy and sustained immune activation has become a major research challenge. This study focuses on leveraging the RDC platform to combine targeted radiation with PD-L1 inhibition, aiming to induce immunogenic cell death through radiation while blocking PD-L1–mediated immune escape, thereby achieving a “radiotherapy + immunotherapy” dual effect.

 

 

Research Methods and Experiments

The authors conducted a systematic search of the PubMed and ClinicalTrials.gov databases, integrating preclinical and clinical data up to January 2026, covering all relevant radioactive elements in the periodic table. The study analyzes the four key components of RDCs: targeting vectors, linkers, chelators, and radionuclides, and categorizes their applications in lung cancer based on target specificity. Experimental systems included various animal models such as patient-derived xenograft (PDX) models, NSCLC cell line–derived models, and small cell lung cancer (SCLC) patient-derived organoid models, used to evaluate biodistribution, tumor uptake, and therapeutic responses of RDCs.

Key Conclusions and Perspectives

• In completed clinical trials, RDCs have evolved from early use of 131I/90Y-labeled antibodies to predominantly 177Lu-labeled SSTR-targeting peptides, demonstrating improved safety and tumor specificity. [Data discovery] + [Implications for subsequent clinical translation pathways]
• PD-L1, as an emerging target, shows enhanced antitumor immune responses in preclinical models with PD-L1-targeted RDCs such as 225Ac-HEHA-PD-L1-i and 177Lu-DOTA-PD-L1-i, suggesting potential synergy with immune checkpoint inhibitors. [Data discovery] + [Implications for future combination immunotherapies]
• The use of novel chelators like HEHA enhances the in vivo stability of 225Ac, reducing off-target toxicity and providing technical support for developing high-safety alpha-emitting RDCs. [Data discovery] + [Implications for future drug design]
• Bispecific antibodies (e.g., 225Ac-FPI-2068) that simultaneously target EGFR and c-MET improve coverage of heterogeneous tumors, overcoming immune escape via single-target inhibition. [Data discovery] + [Implications for future resistance mechanism studies]

Research Significance and Prospects

This study provides a clear RDC design framework for drug development, emphasizing the importance of personalized dosing, multifunctional delivery platforms, and combination strategies. Future RDCs may not only serve as salvage therapy for advanced lung cancer but also enter first-line combination regimens, particularly when paired with immunotherapy to initiate a “radiation vaccine effect.”

For clinical monitoring, theranostic pairs based on the same targeting vector (e.g., 68Ga/177Lu-DOTA-PD-L1-i) could enable pre-treatment patient selection and dynamic assessment of therapeutic response, advancing precision medicine toward a closed-loop system. Furthermore, this platform could be extended to other immune checkpoint molecules such as LAG3 or TIM3, enabling the construction of next-generation immuno-radiotherapeutic systems.

 

 

Conclusion

Radionuclide-drug conjugates represent a pivotal pathway in the evolution of lung cancer treatment from conventional radiotherapy toward precision “theranostics.” This study demonstrates that PD-L1–targeted RDCs can not only precisely kill tumor cells but also reshape the immune microenvironment and break immune tolerance. By combining the high linear energy transfer of alpha particles with immune checkpoint blockade, these bifunctional agents have the potential to overcome limitations of current therapies, especially in refractory or recurrent lung cancers. Future research should focus on further optimizing the match between radionuclide half-life and pharmacokinetics, improving tumor uptake while minimizing renal toxicity. Additionally, individualized dosing plans and multimodal imaging guidance will enhance the therapeutic window. Overall, the RDC platform is emerging as a key pillar in comprehensive lung cancer management, driving the transition from “one-size-fits-all” treatment toward a “personalized, dynamic, and systematic” care model, ultimately offering patients longer survival and improved quality of life.

 

Junzhi Liu, Xiaoyu Zuo, Xue Yang, Lu Gan, and Jianxin Xue. Radionuclide‑drug conjugates in lung cancer: advances in precision therapy and clinical translation. Molecular Cancer.