Mechanism of action and future perspectives of ADCs in combination with immune checkpoint inhibitors for solid tumors

Sep 23, 2026

Uploaded by Callum

Antibody–drug conjugates (ADCs) offer targeted delivery of cytotoxic drugs to tumor cells, but resistance limits durable benefit, making combination strategies necessary. Strong biological rationale indicates ADCs can stimulate immune responses via immunogenic cell death, dendritic cell activation, and memory T-cell activation, enabling long-term anti-tumor immunity. Preclinical findings and ongoing clinical trials combine ADCs with immune checkpoint inhibitors (ICIs) across breast, gastric, and non-small-cell lung cancers. The review summarizes synergistic mechanisms, available clinical evidence by target, re-challenge approaches, and optimized ADC design options.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages19

Reading Time48 min

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Abstract

Introduction

Biological mechanisms of ADCs combined with ICIs

Clinical and Experimental Medicine (2025) 25:139 [https://doi.org/10.1007/s10238-025-01655-6](https://doi.org/10.1007/s10238-025-01655-6) Mechanism of action and future perspectives ofADCs in combination with immune checkpoint inhibitors for solid tumors Yahui Lv1,2,3 · Xiaoran Cui3,4 · Tao Li1,3,5,6 · Chang Liu1,3,8 · An Wang1,3 · Ting Wang1,3,8 · Xin Zhou1,3 · Ruixin Li1,3 · Fan Zhang1,3 · Yi Hu1,3 · Tong Zhang3,5 · Zhefeng Liu1,3,7 Received: 12 February 2025 / Accepted: 26 March 2025 / Published online: 4 May 2025 © The Author(s) 2025 Abstract Antibody–drug conjugates (ADCs) are a promising cancer therapy for targeted delivery of drugs to tumor cells. However, resistance to ADCs remains a challenge, necessitating the exploration of combination therapies. A strong biological theory suggests that ADCs interact with cancer cells and immune cells by triggering mechanisms such as immunogenic cell death, dendritic cell activation, and memory T-cell activation, resulting in long-term anti-tumor immunity and ultimately potential synergistic effects with immunotherapy. Based on extensive and reliable preclinical data, several clinical trials are currently combining ADCs with immune checkpoint inhibitors (ICIs) for the treatment of various cancers, including breast, gastric, and non-small-cell lung cancers, to evaluate the safety and anti-tumor activity of the combination therapy. Preliminary evidence from early clinical trials has reported more effective efficacy data. This paper reviews the combination of ADCs and immunotherapy, highlights the key mechanisms by which the two act synergistically, and summarizes the available clinical evidence against different ADCs targets. The paper also explores the re-challenges used for combination therapies and optimized design options for ADCs drugs. Keywords Antibody-drug conjugates · Immunotherapy · Immune checkpoint inhibitors · Solid tumor Introduction ICIs, represented by PD-1/PD-L1 inhibitors, are a class of drugs that activate immune cells to exert anti-tumor effects by blocking the binding of immune checkpoints to their ligands and relieving immune suppression caused by immune checkpoints [1] . Unfortunately, however, only a fraction of patients could be able to achieve clinical benefit, and there is still a need to explore combination therapy with other drugs or different therapeutic strategies to overcome their resistance and expand their clinical utility [2, 3]. In recent years, novel antibody-based macromolecular complexes represented by ADCs have attracted increasing attention. The drug is composed of an antibody, a payload (a highly potent cytotoxic drug molecule) anda linker connecting the two [4] . The mechanism of action utilizes the binding of antibodies to antigens on the surface of target cells, where ADCs are internalized and release Yahui Lv, Xiaoran Cui and Tao Li have contributed equally to this work. Extended author information available on the last page of the article their payloads, thus exerting cytotoxic effects [5], providing an efficient and precise therapeutic strategy for a wide range of solid tumors [6] . Since the first approval of ADCs for the treatment of solid tumors in 2013 [7], nine ADCshave been approved for advanced solid tumors with different indications, which was showed in the Fig. 1. However, drug resistance is still difficult to avoid [8] . Relevant studies have shown that ADCs not only trigger tumor cell death by targeting antigens and releasing payloads, but also induce immunogenic cell death (ICD), which alters the tumor microenvironment and enhances the anti-tumor immune response. ICIs could release immunosuppression and further exert synergistic effects by activating T cells [9 , 10], and the combined application of the two has become a research hotspot in the field of cancer therapy. This combination therapy has demonstrated significant efficacy against refractory solid tumors in several clinical trials, along with a fa

FAQs

Which clinical evidence is discussed in the review?

The review summarizes ongoing and early clinical trial evidence evaluating safety and anti-tumor activity of ADCs plus ICIs in multiple solid tumor types, including breast, gastric, and non-small-cell lung cancers.

Sep 23, 2026

Uploaded by Callum