Blockade of the PD-1/PD-L1 (Programmed Cell Death Protein-1/Ligand-1) immune checkpoint (IC) axis with monoclonal antibodies (mAbs) has revolutionized cancer treatment. However, due to tumor escape, only 20-30% of patients are predicted to respond favorably. This resistance is commonly associated with tumors lacking T cell infiltration characterized by a "cold" immunosuppressive tumor microenvironment (TME). Here, we highlight combinatorial antibody-based strategies to boost PD-1/PD-L1 blockade efficacy and promote "hot" immunogenic TME. These include mAb co-administration and bispecific formats.
Antibody combinations
As CTLA-4, another IC, inhibits T cell activation in a non-redundant manner to PD-1, dual checkpoint blockade strategies have been evaluated to boost antitumor immune responses1,2. In CheckMate studies, the combination of anti-PD-1 (Nivolumab) and anti-CTLA-4 (Ipilimumab) has demonstrated superior efficacy over monotherapies, especially in PD-L1low melanoma patients2. However, this combotherapy induces higher-grade immune-related adverse effects than monotherapies1-3. Despite this concern, the FDA (USA) has approved Nivolumab and Ipilimumab co-administration in various cancers, including melanona and non small cell lung cancer (NSCLC)1,3. In HIMALAYA studies, the combination of anti-PD-1 (Nivolumab) and a less toxic anti-CTLA-4 (Tremelimumab)4 has led to significantly improved overall survival in cases of advanced or unresectable hepatocellular caricoma (HCC) compared to a standard kinase inhibitor treatment. This combotherapy has been FDA approved for HCC5, and is currently under clinical evaluation for NSCLC.
Altogether, these studies highlight the need for continuous development of new IC blocking mAbs and optimized treatment regimens to balance efficacy and safety1,3.
Bispecific antibodies
The success of bispecific antibodies (bsAbs) in the treatment of hematologic malignancies has spurred the evaluation of various bsAbs formats to cure solid tumors. In addition to better tissue targeting via co-localization or tumor-specific delivery, bsAbs offer multiple advantages, such as simplified dosing, optimized pharmacokinetics, and reduced toxicity. A key area of ongoing innovation lies in identifying the most effective and safest constructs among diverse engineering and targeting strategies6,7.
Simultaneous IC blockade with bsAbs such as anti-PD-1 x CTLA4 (Cadonilimab7) has been tested in clinical trials. COMPASSION studies have revealed encouraging antitumor activity and safety profile of Cadonilimab in cervical cancer patients8.
Other promising bsAbs inhibit PD-1/PD-L1 and VEGF (vascular endothelial growth factor, a key angiogenic factor with immunosuppressive functions). HARMONi studies have shown superior efficacy of Ivonescimab, an anti-PD-1 x VEGF, compared to anti-PD-1 Pembrolizumab alone in NSCLC patients9.
Although no comparative clinical studies have been conducted so far to assess whether bsAbs are associated with better results than the combination of two mAbs, agents such as Cadonilimab and Ivonescimab have been approved by the NMPA (China) for cervical cancer and NSCLC, respectively. While confirmatory studies outside China are needed, the approval of Cadonilimab and Ivonescimab is carrying hope for other designs of anti-PD-1 x CTLA4 (Lorigerlimab, Volrustomig), anti-PD-1 x VEGF (SSGJ-707), or anti-PD-L1 x VEGF (BNT327).
Given the heterogeneity across patients and cancer types, anti-PD-1/PD-L1-based therapies must evolve alongside a deeper understanding of the patient-specific TME to overcome insufficient T cell activation or reinvigorate exhausted T cells. This will guide rational combination strategies and molecular design of next-generation antibody formats. Among these, engineered anti-PD-1 and cytokine fusion proteins (immunocytokines) enable localized immune stimulation, enhancing efficacy while reducing systemic toxicity10. Together, these innovations mark a critical step toward more effective, tailored, and durable cancer immunotherapies.
References
1. Yi, M. et al. 2022. Molecular Cancer. 21(1):28.
2. Wu, K. et al. 2019. Exp Hematol. Oncol. 8(1): 26.
3. Lisi, L. et al., 2022. Pharmacol Res. 175:105997.
4. Xu, C. et al., 2018. BMJ. 363:k4226.
5. France NL., et al., 2024. Target Oncol. 19(1) :115.
6. Li, T. et al., 2024. Cell Commun Signal. 22(1):179.
7. Goebeler, M.E. et al., 2024. Nat Rev Clin Oncol, 21(7):539.
8. Gao, X. et al., 2023. Lancet Oncol. 24(10):1134.
9. Xiong, A. et al., 2025. Lancet. 405(10481):839.
10. Shi, W. et al., 2024. Acta Pharmaceutica Sinica B. 14(11):4649.
