Core Viewpoint - The article discusses the advancements in Antibody-drug conjugates (ADCs) in cancer treatment, highlighting their effectiveness over traditional chemotherapy and their potential in various cancer types [2][16]. Group 1: ADC in Non-Small Cell Lung Cancer (NSCLC) - A study published on December 16, 2025, indicates that ADCs outperform chemotherapy in EGFR-TKI resistant NSCLC, based on a Bayesian network meta-analysis involving 19 randomized controlled trials with 4,039 participants [5][6]. - The ADC Sac-TMT significantly improved progression-free survival (PFS) and overall survival (OS) compared to traditional chemotherapy and other treatment strategies [6][7]. - The study concludes that Sac-TMT, Dato-DXd, and bispecific antibody-based treatments are the most effective options for advanced NSCLC patients who have progressed after EGFR-TKI therapy, with manageable toxicity [7]. Group 2: ADC and PD-1 Inhibitors in Metastatic Urothelial Carcinoma (mUC) - A study published on November 29, 2025, evaluates the combination of the ADC Disitamab Vedotin with PD-1 inhibitors in mUC, showing promising results in a cohort of 63 patients [9][11]. - The treatment response rates included 19.0% achieving complete response (CR) and 52.4% achieving partial response (PR), with an overall response rate (ORR) of 71.4% and disease control rate (DCR) of 87.3% [11][12]. - The study concludes that this combination therapy demonstrates good efficacy and controllable safety as a first-line treatment for mUC patients [12]. Group 3: ADC in HER2-Positive and HER2-Low Advanced Breast Cancer - A study published on February 28, 2025, assesses the efficacy and safety of T-DXd in Chinese patients with HER2-positive and HER2-low advanced breast cancer, involving 61 participants [14][15]. - The results show a median PFS of 10.51 months for the HER2-low group and 10.18 months for the HER2-positive group, with ORR of 37.93% and 62.50% respectively [14][15]. - The study indicates that T-DXd may be an effective treatment option for advanced breast cancer patients regardless of HER2 expression levels, with manageable adverse reactions [15].

Core Viewpoint - The article discusses the challenges and innovative solutions related to Antibody-drug conjugates (ADCs) in precision cancer therapy, highlighting their potential and limitations in clinical applications [4][22]. Group 1: ADC Overview - ADCs combine the specificity of antibodies with the potency of cytotoxic drugs, aiming to improve cancer treatment by targeting tumor cells while minimizing damage to healthy cells [6][7]. - As of 2024, 15 ADCs have been approved globally, with 12 receiving FDA approval, and over 1000 ADCs are under research, including 268 in clinical trials [8]. Group 2: Mechanism of Action - ADCs specifically bind to tumor-associated antigens on cancer cells, leading to internalization and release of cytotoxic payloads that induce cell death [12]. - The modular structure of ADCs includes an antibody for targeting, a linker for payload delivery, and a cytotoxic agent [10]. Group 3: Challenges in ADC Efficacy - Key challenges affecting ADC efficacy include: - Antibody "streaming" effect, where antibodies bind to normal tissues, reducing drug availability at tumor sites [14]. - Binding site barrier effect, limiting drug penetration into tumors due to high affinity binding near blood vessels [14]. - Tumor heterogeneity, leading to inconsistent antigen expression and variable ADC uptake [14]. - Downregulation of target antigens by tumor cells, affecting binding and internalization [14]. Group 4: Optimization Strategies - Strategies to enhance ADC specificity and reduce off-target toxicity include: - Improving linker stability and reducing toxicity through various responsive linkers [16]. - Utilizing tumor microenvironment (TME) triggers for controlled release of the drug [16]. - Implementing emerging payload strategies like immune-stimulating ADCs (ISAC) and degradation-inducing ADCs (DAC) [18][22]. Group 5: Future Directions - The article emphasizes the need for a deeper understanding of tumor delivery barriers and bridging the gap between preclinical and clinical studies to fully realize the potential of ADCs in precision oncology [22].