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

Abstract

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.

Mechanistic PBPK Modeling of Antibody–Drug Conjugates: Integration of Antibody Disposition, Linker Deconjugation, and Payload Pharmacokinetics
Toxics1 Oct 2026Peer-reviewedCC BYFull textPharmacology & toxicologyEurope PMC
Recent advances in function-enhanced antibody-drug conjugates: Antibody optimization and payload combination
Xin-tong Liu, Feng Tang, Wei Huang
Acta Pharmacologica Sinica17 Jul 2026Peer-reviewedLicence not statedFull text1 citedMedical imaging & radiologyPMC
From Payload‐First Toward Dual‐Mechanism Antibody–Drug Conjugates
Xavier Pivot, Sebastian Jung, Sébastien Harlepp +1
Advanced Materials30 Jun 2026Peer-reviewedCC BY 4.0Full textGeneral biology OncologyHAL
Expanding Antibody-Drug Conjugates Mechanistic Diversity with Verubulin: A Dual Tubulin-Binding and Vascular-Disrupting Payload.
Héloïse Cahuzac, Louis Moreira da Silva, Yoann Colas +10
ChemRxiv23 Oct 2026PreprintCC BY-NC-NDFull textMedical imaging & radiologyChemRxiv
Antibody–drug conjugates in solid tumors: current landscape, challenges, and future directions
Teng Yang, Takaya Shimura, Qing Wei +1
Holistic Integrative Oncology25 Oct 2026Peer-reviewedCC BYFull textMedical imaging & radiologyDOAJ

Cite

BibTeX RIS

BibTeX

@article{waight2026immunological,
  title = {{The immunological landscape of antibody-drug conjugates: from target to payload biology}},
  author = {Jeremy D. Waight and Maria C. Speranza and Christopher B. Hopson and Kenneth W. Hance},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1964101},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1964101/full},
  note = {CC BY 4.0},
}

RIS

TY  - JOUR
TI  - The immunological landscape of antibody-drug conjugates: from target to payload biology
AU  - Jeremy D. Waight
AU  - Maria C. Speranza
AU  - Christopher B. Hopson
AU  - Kenneth W. Hance
PY  - 2026
DA  - 2026/10/27
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1964101
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1964101/full
AB  - 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.
SN  - 1664-3224
ER  -

Abstract

Related

Cite