Role of PD-1/PD-L1 signaling axis in oncogenesis and its targeting by bioactive natural compounds for cancer immunotherapy

Sep 21, 2026

Cancer remains a major global cause of mortality, and immune checkpoint inhibitors have become a cornerstone in oncology. Central to this field is the PD-1/PD-L1 signaling axis, where PD-L1 on tumor cells binds PD-1 to weaken innate immune activity and reshape innate and adaptive immune functions. Monoclonal antibodies targeting PD-1/PD-L1 can trigger autoimmune-like toxicities across organ systems. Natural bioactive compounds that inhibit immune checkpoints may drive tumor apoptosis, alter proliferation, and slow progression. This review synthesizes mechanistic and clinical evidence while addressing knowledge gaps and future research directions.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages51

Reading Time2 h 9 min

AccessFree to download

Abstract

Background

Cancer burden and mortality trends

PD-1/PD-L1 checkpoint biology

Therapeutic targeting

Monoclonal antibodies against PD-1/PD-L1

Natural bioactive compounds targeting PD-1/PD-L1

Future directions and challenges

Godiyal et al. Military Medical Research (2024) 11:82 [https://doi.org/10.1186/s40779-024-00586-9](https://doi.org/10.1186/s40779-024-00586-9) REVIEW Open Access Role of PD-1/PD-L1 signaling axis in oncogenesis and its targeting by bioactive natural compounds for cancer immunotherapy Yogesh Godiyal1, Drishti Maheshwari 1, Hiroaki Taniguchi2,3, Shweta S. Zinzuwadia4, Yanelys Morera‑Díaz5, DeveshTewari1* and Anupam Bishayee4* Abstract Cancer is a global health problem and one of the leading causes of mortality. Immune checkpoint inhibitors have revolutionized the field of oncology, emerging as a powerful treatment strategy. A key pathway that has garnered considerable attention is programmed cell death‑1 (PD‑1)/programmed cell death ligand‑1 (PD‑L1) . The interaction between PD‑L1 expressed on tumor cells and PD‑1 reduces the innate immune response and thus compromises the capability of the body’s immune system. Furthermore, it controls the phenotype and functionality of innate and adaptive immune components. A range of monoclonal antibodies, including avelumab, atezolizumab, camre‑ lizumab, dostarlimab, durvalumab, sinitilimab, toripalimab, and zimberelimab, have been developed for targeting the interaction between PD‑1 and PD‑L1 . These agents can induce a broad spectrum of autoimmune‑like complica‑ tions that may affect any organ system. Recent studies have focused on the effect of various natural compounds that inhibit immune checkpoints. This could contribute to the existing arsenal of anticancer drugs. Several bioactive natural agents have been shown to affect the PD‑1/PD‑L1 signaling axis, promoting tumor cell apoptosis, influenc‑ ing cell proliferation, and eventually leading to tumor cell death and inhibiting cancer progression. However, thereis a substantial knowledge gap regarding the role of different natural compounds targeting PD‑1 in the context of cancer. Hence, this review aims to provide a common connection between PD‑1/PD‑L1 blockade and the antican‑ cer effects of distinct natural molecules. Moreover, the primary focus will be on the underlying mechanism of action as well as the clinical efficacy of bioactive molecules. Current challenges along with the scope of future research directions targeting PD‑1/PD‑L1 interactions through natural substances are also discussed. Keywords Cancer, PD‑1/PD‑L1, Crosstalk, Natural compounds, Therapeutic targets *Correspondence: DeveshTewari [devesh.tewari@dpsru.edu.in](devesh.tewari@dpsru.edu.in); [dtewari3@gmail.com](dtewari3@gmail.com) Anupam Bishayee [abishayee@lecom.edu](abishayee@lecom.edu); [abishayee@gmail.com](abishayee@gmail.com) 1 Department of Pharmacognosy and Phytochemistry, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, New Delhi 110017, India 2 Department of Experimental Embryology, Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, Jastrzebiec, 05‑552 Magdalenka, Poland 3 African Genome Center, Mohammed VI Polytechnic University, Hay Moulay Rachid, 43150 Ben Guerir, Morocco 4 Department of Pharmacology, College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA 5 Clinical Investigation and Biomedical Research Directions, Center for Genetic Engineering and Biotechnology, 11600 Havana, Cuba © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and you

FAQs

How does the PD-1/PD-L1 signaling axis contribute to oncogenesis?

PD-L1 expressed on tumor cells interacts with PD-1, reducing innate immune responses and compromising immune system capability. It also regulates phenotypes and functions of both innate and adaptive immune components.

What immune checkpoint inhibitors are discussed for targeting PD-1/PD-L1?

The review lists monoclonal antibodies such as avelumab, atezolizumab, camrelizumab, dostarlimab, durvalumab, sinitilimab, toripalimab, and zimberelimab.

What is the role of bioactive natural compounds in cancer immunotherapy according to the review?

Natural compounds that inhibit immune checkpoints can affect the PD-1/PD-L1 signaling axis, promoting tumor cell apoptosis and influencing proliferation. They may help inhibit cancer progression, although gaps remain in understanding different natural compounds’ roles.

Sep 21, 2026

Uploaded by Clementine