103: Bidirectional interaction of �-opioids and anti-PD-1:reduced antitumor activity and opioid analgesia

Topic: Basic Science
Subtopic: Non-specific to any diagnosis (including studies in healthy animals), Neuroimmunology

Background and Aims: Immune checkpoint inhibitors (ICIs), particularly PD-1 blockade, have substantially improved clinical outcomes in cancer. However, accumulating clinical evidence indicates that concomitant opioid administration may compromise their antitumor efficacy. In contrast, the impact of immune checkpoint inhibition on opioid-mediated analgesia remains poorly defined. In this study, we tested the hypothesis that opioids and PD-1 blockade engage in bidirectional crosstalk mediated by peripheral μ-opioid receptor (MOR)–dependent neuroimmune signaling.

Methods: Tumor-bearing mice were treated with anti–PD-1 antibody in the presence or absence of opioid analgesics. To delineate the contribution of peripheral MOR signaling, the peripherally restricted MOR antagonist naldemedine, a prototypical peripherally acting MOR antagonist (PAMORA), was administered. Tumor progression, nociceptive thresholds, analgesic responses, and immune parameters were systematically evaluated.

Results: Morphine administration markedly diminished the antitumor efficacy of PD-1 blockade. This impairment was partially reversed by naldemedine, implicating peripheral MOR signaling as a critical mediator of opioid-induced suppression of antitumor immunity. Notably, PD-1 blockade alone lowered pain thresholds and further attenuated morphine-induced analgesia, indicating that immune checkpoint inhibition actively modulates opioid responsiveness. Ongoing studies are investigating whether pharmacological inhibition of peripheral MOR signaling can restore opioid analgesic efficacy under PD-1 blockade.

Conclusions: These findings reveal a previously unrecognized bidirectional interaction between cancer immunotherapy and opioid-mediated analgesia. This interaction appears to be orchestrated through peripheral MOR-dependent neuroimmune crosstalk, positioning peripheral MOR signaling as a functional interface between the nervous and immune systems. Targeting this axis with PAMORAs may represent a rational strategy to preserve antitumor immunity while maintaining effective pain control in cancer patients.

References: No references are cited in this abstract.

Presenting Author: Yusuke Hamada
Submitting Author: Yusuke Hamada

Senior Author: Minoru Narita

IASP 2026 Global Year theme of Neuropathic Pain: Yes

• Misaki Itagaki - Department of Pharmacology, Hoshi University
• Yukari Suda: Ph.D. - Department of Pharmacology, Hoshi University / Laboratory of Cancer Pathophysiology, National Cancer Center Research Institute
• Michiko Narita - Laboratory of Cancer Pathophysiology, National Cancer Center Research Institute
• Mitsuaki Yamazaki: M.D., Ph.D - Department of Anesthesiology, Toyama Nishi General Hospital
• Naoko Kuzumaki: Ph.D. - Department of Pharmacology, Hoshi University / Laboratory of Cancer Pathophysiology, National Cancer Center Research Institute
• Minoru Narita: Ph.D. - Department of Pharmacology, Hoshi University / Laboratory of Cancer Pathophysiology, National Cancer Center Research Institute