The immunological landscape of antibody-drug conjugates: from target to payload biology

Antibody-drug conjugates (ADCs) have the potential to impact biology well beyond targeted cytotoxin delivery. Here, we discuss considerations for ADC immune interplay, from Fc biology to elicitation of immunogenic cell death (ICD), to manipulation of the tumor microenvironment. In recent years, antibody-drug conjugates (ADCs) have garnered significant attention as a major therapeutic modality in oncology. By combining a targeting mechanism with various classes of small-molecule payloads, ADCs offer a highly modular approach to either selectively deliver (or promote accumulation of) chemotherapeutic agents to tumors, fueling a dramatic expansion in ADC clinical development. With hundreds of candidates now progressing through clinical testing in solid tumors and hematologic malignancies, a more nuanced understanding of ADC biology is starting to take shape. Despite the relatively simplistic design, even modest changes to the antibody and/or warhead-linker-payload (WLP) design can result in significant biological variance. Instead of just scaffolds for drug delivery, a growing body of evidence supports a multifaceted role for ADCs, including a mechanistic relationship with the immune system. Here, we discuss considerations for ADC immune interplay, from Fc biology to elicitation of immunogenic cell death (ICD), to influence on the tumor microenvironment (TME). Finally, we explore the translational challenges of optimizing ADC–immunotherapy combinations, including payload selection, linker design, and safety considerations for combination regimens. Collectively, this review explores the evolving understanding of immunomodulatory characteristics of ADCs and their potential to bridge targeted therapy and cancer immunology.