Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2025;20(1):1-25.
doi: 10.2174/0115748928269276231120103256.

Mechanisms of Anti-PD Therapy Resistance in Digestive System Neoplasms

Yuxia Wu  1 , Xiangyan Jiang  1 , Zeyuan Yu  1 , Zongrui Xing  1 , Yong Ma  1 , Huiguo Qing  1
Affiliations
Review

Mechanisms of Anti-PD Therapy Resistance in Digestive System Neoplasms

Yuxia Wu et al. Recent Pat Anticancer Drug Discov. 2025.

Abstract

Digestive system neoplasms are highly heterogeneous and exhibit complex resistance mechanisms that render anti-programmed cell death protein (PD) therapies poorly effective. The tumor microenvironment (TME) plays a pivotal role in tumor development, apart from supplying energy for tumor proliferation and impeding the body's anti-tumor immune response, the TME actively facilitates tumor progression and immune escape via diverse pathways, which include the modulation of heritable gene expression alterations and the intricate interplay with the gut microbiota. In this review, we aim to elucidate the mechanisms underlying drug resistance in digestive tumors, focusing on immune-mediated resistance, microbial crosstalk, metabolism, and epigenetics. We will highlight the unique characteristics of each digestive tumor and emphasize the significance of the tumor immune microenvironment (TIME). Furthermore, we will discuss the current therapeutic strategies that hold promise for combination with cancer immune normalization therapies. This review aims to provide a thorough understanding of the resistance mechanisms in digestive tumors and offer insights into potential therapeutic interventions.

Keywords: Immunotherapy resistance; PD-1/B7-H1; anti-PD-1/PD-L1 therapy; digestive system neoplasms; normalization cancer immunotherapy; pancreatic cancer..

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest, financial or otherwise.

Figures

Fig. (1)
Fig. (1)
Immune-mediated mechanisms of drug resistance.
Fig. (2)
Fig. (2)
Mechanisms of drug resistance associated with microbiota.
Fig. (3)
Fig. (3)
Mechanisms of drug resistance associated with metabolism.
Fig. (4)
Fig. (4)
Mechanisms of drug resistance associated with epigenetics.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Rebecca L, Siegel MPH, Kimberly D, Miller MPH. Nikita Sandeep Wagle MBBS, M., PhD, Ahmedin Jemal DVM, PhD Cancer statistics, 2022;2023
    1. Kalafati L., Kourtzelis I., Schulte-Schrepping J., et al. Innate immune training of granulopoiesis promotes anti-tumor activity. Cell. 2020;183(3):771–785.e12. doi: 10.1016/j.cell.2020.09.058. - DOI - PMC - PubMed
    1. Leko V., Rosenberg S.A. Identifying and targeting human tumor antigens for t cell-based immunotherapy of solid tumors. Cancer Cell. 2020;38(4):454–472. doi: 10.1016/j.ccell.2020.07.013. - DOI - PMC - PubMed
    1. Schürch C.M., Bhate S.S., Barlow G.L., et al. Coordinated cellular neighborhoods orchestrate antitumoral immunity at the colorectal cancer invasive front. Cell. 2020;182(5):1341–1359.e19. doi: 10.1016/j.cell.2020.07.005. - DOI - PMC - PubMed
    1. El-Khoueiry A.B., Sangro B., Yau T., et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): An open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389(10088):2492–2502. doi: 10.1016/S0140-6736(17)31046-2. - DOI - PMC - PubMed

MeSH terms

Substances

LinkOut - more resources