Chemotherapy combined with immunotherapy as a neoadjuvant strategy for locally advanced head and neck squamous cell carcinoma significantly improves pathological remission rates, but faces a "triple dilemma"—large differences in patient response to treatment, additive drug toxicity affecting quality of life, complex and difficult to crack resistance mechanisms, how to enable patients to achieve "long-term benefits" remains a clinical breakthrough urgently needed.

On August 25,team of Xu Fang,associate professor of Faculty of Life and Health Sciences, Shenzhen University of Advanced Technology, and associate researcher of Shenzhen Institutes of Advanced Technology (SIAT), Chinese Academy of Sciences,and collaborators published the latest results inNature Medicine, for thefirst time confirming that immune senescence in the tumor microenvironment is a key factor leading to immunotherapy resistance, and through animal models and the world's first Phase II clinical trial confirmed that anti-aging drugs combined with immunotherapy not only significantly improve the treatment response rate in head and neck squamous cell carcinoma patients, but also greatly reduce toxic side effects, providing a breakthrough new strategy for solid tumor immunotherapy.

Screenshot of the paper online

Single-cell multi-omics "uncovers" the culprit of resistance

Immune senescence is the key

The starting point of the study stems from the team's deep inquiry into clinical treatment differences. Previously, the research team discovered through a Phase II clinical trial (OOC-001) that although neoadjuvant chemotherapy combined with immunotherapy achieved a 47.9% pathological complete remission rate in head and neck squamous cell carcinoma patients, some patients still had no response to treatment. Why do the same treatment regimens show such large differences in patient responses?

To unravel this mystery, the research team conducted single-cell multi-omics analysis and finally locked onto"immune senescence"as the key factor. The analysis results show that in the tumor microenvironment of non-responsive patients, immune senescence features are extremely obvious:

First, depletion of the immune cell "reserve pool"

The proportion of CCR7⁺CD4⁺ naive T cells (the "initial force" responsible for initiating immune responses) and CD27⁺ memory B cells (key cells for maintaining long-term immune memory) significantly decreased;

Second, "shrinkage" of immune diversity

Decreased clonal diversity of T cell receptors (TCR) and B cell receptors (BCR), meaning weakened ability of immune cells to recognize and attack tumors;

Third, "exceeding standards" of senescence markers

Significantly elevated expression levels of senescence-related proteins such as p16/p21.

In addition, the research team also constructed an immune senescence-related gene set (IAGs) scoring system, confirming that T cells and B cells in non-responsive patients have higher IAGs scores, and found that the increase in IGF1⁺ macrophage proportion is negatively correlated with the decrease in CD4⁺ naive T cells. This series of findings clearly reveals that immune senescence is a key mechanism leading to treatment resistance, providing precise targets for the formulation of subsequent intervention strategies.

Animal Model Validation

Anti-Aging Drug DQ + PD-1 Inhibitor

Successfully Reverses Immune Senescence

Having identified the resistance mechanism, the research team randomly conducted preclinical validation of intervention strategies, testing the combined efficacy of "anti-aging drugs + immunotherapy" in various animal models—in a 4-nitroquinoline-1-oxide (4-NQO)-induced head and neck squamous cell carcinoma aging mouse model, the team used PD-1 inhibitors (commonly used immunotherapy drugs) in combination with dasatinib and quercetin (D+Q, a classic anti-aging drug combination), with exciting results, not only achieving significant tumor control but also successfully reversing immune senescence.

Specifically, compared to using PD-1 inhibitors alone or in combination with chemotherapy, the treatment with PD-1 inhibitors combined with dasatinib and quercetin (D+Q) significantly reduced tumor lesions and prolonged survival; this combination therapy reduced the expression of senescence markers in immune cells within the tumor while increasing the proportion of CD62L⁺CD44⁻ naive CD4⁺ T cells, indicating that the "new force" of immune cells was replenished, and immune response capabilities were restored.

More importantly,this effect is not limited to the head and neck cancer model.In the Ercc1+/- premature aging mouse model, bladder cancer, and breast cancer transplant models, the D+Q+PD-1 combination regimen demonstrated similar reversal of immune senescence and enhanced anti-tumor immune effects, confirming the strategy’s potential to extend to various solid tumors.

Phase II Clinical Trial Confirmation

33.3% Pathological Remission Rate

Significantly Reduced Side Effects

Based on the positive results of preclinical studies, the research team conducted the world’s first Phase II clinical trial of anti-aging drugs combined with immunotherapy (COIS-01), aiming to validate the safety and efficacy of this strategy in humans.

The trial included 24 patients with resectable head and neck squamous cell carcinoma, adopting a neoadjuvant treatment regimen of"tislelizumab + dasatinib + quercetin". The results showed that this regimen demonstrated significant advantages of high efficacy and low toxicity:

First, a significantly improved treatment response rate

33.3% achieved major pathological remission, including a 16.7% pathological complete remission rate, which is significantly better than historical data for immunotherapy alone.

Second, significantly reduced toxic side effects

The incidence of grade 3-4 treatment-related adverse events in this regimen was only 4.2%, far lower than the 51% side effect rate of traditional chemotherapy combined with immunotherapy.

Third, the mechanism was clinically validated

Through immunohistochemical analysis, an increase in CCR7⁺ naive T cells and a decrease in senescence marker expression were observed in the tumor post-treatment, providing strong support for the clinical translation of the innovative combination strategy.

Opening a New Direction for Solid Tumor Treatment

Three Promising Future Exploration Directions

This study, through two investigator-initiated Phase II clinical trials, combined with single-cell multi-omics analysis and animal model experiments, systematically revealed for the first time the critical role of immune senescence in tumor immunotherapy resistance, and innovatively proposed a new strategy of combining anti-aging drugs with immunotherapy. This not only broughthigh-efficacy, low-toxicitynew treatment options for head and neck squamous cell carcinoma patients but also opened a new direction for"immunotherapy + anti-aging"treatment of solid tumors.

Preliminary clinical data show that this combination regimen not only improved pathological remission rates but also significantly reduced treatment-related side effects, demonstrating strong translational potential. Meanwhile, based on various solid tumor models, the long-term survival rate of COIS-01 is also promising.

Xu Fangstated that based on the current research results, future efforts will focus on three major directions for in-depth exploration:First,screen more potent anti-immune senescence targeted drugs, further explore more precise and effective immune senescence intervention targets to enhance the efficacy of combination therapy;Second,optimize treatment regimen details, conducting refined studies on drug dosage and administration frequency to further reduce side effects while ensuring efficacy;Third,expand treatment application scenarios: Explore the application of this combination strategy in postoperative maintenance therapy, consolidation therapy after standard treatment, and other scenarios.

Graduate students Liu Niu, Wu Jiaying, Zhong Jianglong, Wei Bin, Cai Tingting from the Department of Oral Medicine at Sun Yat-sen Memorial Hospital of Sun Yat-sen University, and doctoral student Deng Enze from Guangzhou National Laboratory are the first authors; Xu Fang, Chief Physician Fan Song from the Department of Oral Medicine at Sun Yat-sen Memorial Hospital of Sun Yat-sen University, researcher Fan Xiaoying from Guangzhou National Laboratory, and Professor Xinhui Wang from Harvard Medical School are the corresponding authors. The research was supported by projects such as Shenzhen City’s “Outstanding Youth” and Shenzhen Medical Special Funds.

Paper link: https://www.nature.com/articles/s41591-025-03873-7 (click "Read Original" to view)

Source: Faculty of Life and Health Sciences

Editor: Wang Lu

Reviewed by: Meng Qianyu, Wei Guanyu, Wang Zhikang