At the 2025 American Association for Cancer Research (AACR) annual meeting, the innovative combination strategy of antibody-drug conjugates (ADCs) and immunotherapy emerged as a major highlight. This approach not only demonstrated powerful synergistic anti-tumor potential but also signaled a new era in cancer treatment.
Recent clinical and preclinical research has revealed ADCs’ unique dual mechanism of action: they not only precisely deliver cytotoxic payloads into tumor cells for direct cell killing but also induce immunogenic cell death (ICD), releasing tumor-associated antigens and thereby “activating” the immune system. When combined with advanced immunotherapies such as immune checkpoint inhibitors, T cell co-stimulatory molecules, or bispecific antibodies, these properties trigger significant immune activation within the tumor microenvironment—effectively overcoming resistance issues seen in so-called “cold tumors”. This growing field increasingly relies on in vitro drug combination screening to identify synergistic treatment pairs before advancing to animal or clinical studies.
HER2 Target: From Biological Mechanism to Therapeutic Breakthrough
HER2 (human epidermal growth factor receptor 2) is a tyrosine kinase receptor. Its overexpression persistently activates downstream signaling pathways that drive cell proliferation, survival, and metastasis—closely linked to aggressive cancers like breast and gastric cancers. Decades of HER2-targeted drug development have evolved from monoclonal antibodies (e.g., trastuzumab) and small molecule inhibitors (e.g., lapatinib) to today’s ADC drugs, continuously upgrading treatment strategies.
ADCs, with their dual advantage of “precise targeting + potent cytotoxicity,” have become a cornerstone in treating HER2-positive tumors. Represented by drugs like T-DM1 (ado-trastuzumab emtansine) and Enhertu, these therapies deliver cytotoxic agents via antibody targeting, significantly improving efficacy while reducing systemic toxicity. However, monotherapies still face challenges like resistance and suboptimal response rates. Combination immunotherapy (e.g., PD-1/PD-L1 inhibitors) has emerged as a breakthrough direction—activating immune responses in the tumor microenvironment to achieve synergistic effects greater than the sum of individual therapies.
Preclinical data suggest that Enhertu, an anti-cancer ADC, enhances anti-tumor immunity. When used in combination with PD-1 antibodies, it shows superior efficacy compared to monotherapy. Enhertu, in tandem with immunotherapies targeting the PD-1/PD-L1 pathway, demonstrates a synergistic effect—killing tumor cells while enhancing tumor immunogenicity. According to interim analysis from the phase 1b DS8201-A-U106 study (NCT04042701) presented at the 2024 ESMO Immuno-Oncology Congress, the Enhertu + pembrolizumab combination exhibited anti-tumor activity in non-small cell lung cancer (NSCLC) patients with HER2 expression or mutations.
Global pharmaceutical companies are accelerating efforts in combining HER2-targeted ADCs with immunotherapy. Roche’s T-DM1 plus atezolizumab (a PD-L1 inhibitor) is in phase III trials for triple-negative breast cancer. RemeGen’s disitamab vedotin (RC48) in combination with toripalimab shows promise in gastric and urothelial cancers. Domestic ADCs such as A166 from Kelun-Biotech and SHR-A1811 from Hengrui Medicine have also initiated early-stage trials in combination immunotherapy.
However, the complexity of combination therapy mechanisms demands reliable preclinical models to assess efficacy and safety. To support the development of HER2-targeted inhibitors or ADC-immunotherapy combinations, Kyinno Biotechnology leverages its robust engineered cell line capabilities to build tumor cell lines such as CT26-hHER2. Backed by antibody discovery and in vivo/in vitro pharmacology platforms, Kyinno provides end-to-end solutions for target-based research. Contact us for more information.
The CT26-hHER2 Model This model was created by stably transfecting the human HER2 gene into the CT26 murine colon carcinoma cell line, establishing a syngeneic tumor model with high HER2 expression. With stable HER2 expression and reliable tumor formation, it serves as a top-tier platform for validating the synergy of ADCs and immunotherapies, offering key advantages:
- Clinically Relevant Targeting: Human HER2 ensures specific binding of ADCs without cross-species interference.
- Intact Immune System: Suitable for combination immunotherapy research, enabling simultaneous evaluation of tumor regression and immune cell infiltration.
- High-Quality Data: High tumor take rate and short modeling cycle support large-scale efficacy screening and mechanism studies.
Using this model, researchers have validated the synergistic effects of multiple ADC drugs with PD-1 inhibitors, providing essential preclinical evidence for clinical translation.
CT26-ERBB2-GFP-Luc CDX Model
JIMT1 CDX Model
NCI-H1781 CDX Model
NCI-N87 CDX Model
As multi-mechanism integration and combination therapy strategies advance, ADCs are transforming from traditional “targeted delivery tools” into dual-function agents that combine targeted therapy with immune activation. This marks a significant shift in ADC therapy models and builds a crucial bridge between precision medicine and immune modulation. Looking ahead, this strategy holds promise to bring renewed hope and treatment possibilities to more patients.
