Antibody-oligonucleotide conjugates in cancer therapy: Potential and Promise.

X-Drug Conjugates (XDCs) achieve precise therapy through a modular design comprising three key components: targeting vehicle, linker, and therapeutic payload. Among these, Antibody-Drug Conjugate (ADCs) have demonstrated the most remarkable progress in clinical research. By leveraging their precise targeting mechanism and robust clinical data, ADCs have emerged as frontrunner therapeutics in oncology. Building upon this success, Antibody-Oligonucleotide Conjugates (AOCs) represent an innovative evolution-replacing traditional cytotoxic payloads with gene-modulating oligonucleotides, such as small interfering RNA (siRNA) and antisense oligonucleotides (ASO). This paradigm shift transitions the therapeutic focus from "cell killing" to "gene regulation", opening new avenues for cancer treatment. In this review, we provide an overview of the biology and chemistry of AOCs, examine the key components of AOC design (including the antibody, linker and conjugation chemistry, and oligonucleotides, and highlight promising AOC candidates currently in clinical development for cancer treatment while evaluating both the challenges and opportunities. By discussing recent advances in AOCs, we offer valuable insights into future directions for this innovative class of immunoconjugates and their potential to revolutionize targeted cancer therapies.