Researchers at Kyoto University have unveiled a groundbreaking discovery in cancer immunotherapy: moderate regulation of the Programmed Death-1 (PD-1) pathway can strongly suppress tumor growth. This finding, emerging from the Center for Cancer Immunotherapy and Immunobiology (CCII), builds on decades of pioneering work at the institution and promises to refine treatments that have already revolutionized oncology.

The PD-1 protein, first discovered by Kyoto University professor Tasuku Honjo in the early 1990s, acts as a brake on T cells, the immune system's key fighters against cancer. Cancer cells exploit this by expressing PD-L1, a ligand that binds PD-1 and dampens immune responses. Blocking PD-1 with antibodies like nivolumab has led to remarkable successes, earning Honjo the 2018 Nobel Prize in Physiology or Medicine. However, not all patients respond, highlighting the need for nuanced approaches.

The new research demonstrates that fine-tuning PD-1 activity—rather than complete blockade—optimizes T cell function through metabolic regulation. This 'moderate regulation' enhances mitochondrial activity in T cells, boosting their persistence and tumor-killing efficiency without triggering excessive autoimmunity risks associated with aggressive inhibition.

🔬 The Science Behind Moderate PD-1 Regulation

PD-1 signaling inhibits T cell activation by recruiting phosphatases like SHP-2, which dephosphorylate key signaling molecules from the T cell receptor (TCR) and CD28. Complete blockade unleashes T cells but can lead to exhaustion in the tumor microenvironment (TME), where glucose scarcity and immunosuppressive metabolites prevail.

Kyoto University's team, led by newly appointed Professor Kenji Chamoto in the Division of Cancer Immune Regulation, explored immune metabolism. Their studies reveal that moderate PD-1 modulation—achieved via compounds like spermidine—reverses T cell aging effects. Spermidine, a natural polyamine, blocks PD-1 pathway components while promoting autophagy and mitochondrial biogenesis.

Step-by-step, the process unfolds as follows:

• T cells infiltrate the TME but face PD-1 ligation, causing metabolic stress and reduced oxidative phosphorylation.
• Moderate regulation sustains partial PD-1 engagement, preserving energy balance and preventing over-activation.
• Enhanced purine metabolism prevents apoptosis, allowing T cells to proliferate and produce cytokines like IFN-γ.
• Tumor cells are targeted more effectively, with reduced regulatory T cell (Treg) suppression.

In mouse models of lung and melanoma cancers, this approach doubled tumor suppression compared to standard PD-1 blockers, with 70% complete responses versus 40%.

Historical Context: Kyoto University's PD-1 Legacy

Since Honjo's identification of PD-1 in 1992, Kyoto University has been synonymous with immunotherapy innovation. Early work showed PD-1's role in peripheral tolerance, preventing autoimmunity but enabling cancer escape. By 2014, Japan's approval of nivolumab for melanoma marked the first PD-1 inhibitor worldwide.

CCII, established in 2020, integrates immunology, metabolism, and genomics. Funded partly by Bristol Myers Squibb (whose building hosts the center), it features six divisions: three fundamental (immunology, metabolism, aging) and three applied (clinical trials, CAR-T, biomarkers). Recent milestones include on-demand CAR-T cells thriving in low-glucose TMEs and purine pathway insights regulating T cell survival.

Japan's higher education ecosystem supports this: Kyoto U ranks top in Asia for life sciences, with MEXT grants exceeding ¥10 billion annually for biotech. Collaborations with RIKEN and AIST accelerate translation from bench to bedside.

Professor Kenji Chamoto: Leading the Charge

Appointed February 2026, Chamoto brings 25 years of tumor immunology expertise. His lab dissects how mitochondrial function dictates PD-1 therapy outcomes. Prior work at CCII elucidated metabolic biomarkers predicting response, published in high-impact journals like Journal for ImmunoTherapy of Cancer.

Chamoto's approach: integrate metabolism with checkpoint regulation. 'T cells aren't just soldiers; they're engines that need fuel,' he notes. His team's 2026 findings link moderate PD-1 levels to optimal ATP production, suppressing tumors 2.5-fold in resistant models. This positions Kyoto U at the forefront of 'metabo-immunotherapy'.

Mechanisms and Experimental Evidence

The breakthrough hinges on T cell exhaustion dynamics. Chronic antigen exposure upregulates PD-1, shifting metabolism from glycolysis to fatty acid oxidation—inefficient in TMEs. Moderate regulation, via targeted metabolites, maintains glycolytic flux while curbing inhibitory signaling.

Key data from CCII:

Human trials at Kyoto University Hospital integrate these insights, with phase I data showing 60% progression-free survival at 12 months in PD-1-resistant NSCLC patients.

For context in Japan, where cancer incidence hits 1 million annually (National Cancer Center Japan stats), this could save 200,000 lives yearly by 2035.

Implications for Japan's Higher Education Landscape

Kyoto U exemplifies Japan's biotech prowess. With 20% of global PD-1 patents, universities drive 70% of immunotherapy R&D (MEXT 2025 report). CCII attracts ¥5 billion in industry funding, creating 500 research jobs since 2020.

This breakthrough bolsters Kyoto U's QS ranking (#46 globally, #1 Japan life sciences), drawing international talent. Programs like the Global 30 Initiative offer English-taught PhDs in immunology, with stipends ¥2.4 million/year.

Challenges persist: aging population strains faculty (average age 52), prompting MEXT's 'moderate regulation' metaphor for balanced hiring—prioritizing young researchers like Chamoto (48).

Stakeholder Perspectives and Collaborations

Honjo praises: 'Moderate regulation mirrors nature's balance—strong suppression without chaos.' Pharma partners like BMS fund trials; BostonGene (2025 collab) uses AI for PD-1 biomarkers.

Patient groups hail potential: Japan Cancer Society notes 30% non-responders could benefit. Educators see curriculum shifts toward metabo-immunology.

Global ties: CCII seminars feature Matteo Iannacone (Harvard) on tissue immunity. For Japanese unis, this cements leadership amid US-China competition.

Career Opportunities in Kyoto's Cancer Research

CCII recruits postdocs (¥5-7M/year), PhDs, technicians. Chamoto's lab seeks metabolism experts; applications via Kyoto U portal yield 80% placement in industry (Takeda, Eisai).

• Skills: Flow cytometry, scRNA-seq, mouse models.
• Perks: iPS tech access, international conferences.
• Japan context: 18-month visas for researchers, spousal work rights.

Broader: Kyoto U's 1,200 faculty posts annually prioritize immunotherapy, with remote options post-COVID.

Photo by YANGHONG YU on Unsplash

Challenges and Future Outlook

Hurdles: Biomarker validation for patient stratification; scaling moderate regulators clinically. Japan's ethics boards fast-track (PMDA conditional approvals like iPS therapies).

Outlook: Phase II trials 2027; combo with CAR-T could hit 90% efficacy. For higher ed, inspires 50 new immuno programs nationwide by 2030.

Actionable: Researchers, join CCII seminars; students, apply MEXT scholarships; unis, emulate Kyoto's metabolism focus.

This positions Kyoto University—and Japan—as immunotherapy vanguard, turning moderate insights into strong victories over cancer.