Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable efficacy in treating hematological malignancies and is expanding into other indications such as autoimmune diseases, fibrosis, aging and viral infection. However, clinical challenges persist in treating solid tumors, including physical barriers, tumor heterogeneity, poor in vivo persistence, and T-cell exhaustion, all of which hinder therapeutic efficacy. This review focuses on the critical role of tonic signaling in CAR-T therapy. Tonic signaling is a low-level constitutive signaling occurring in both natural and engineered antigen receptors without antigen stimulation. It plays a pivotal role in regulating immune cell homeostasis, exhaustion, persistence, and effector functions. The "Peak Theory" suggests an optimal level of tonic signaling for CAR-T function: while weak tonic signaling may result in poor proliferation and persistence, excessively strong signaling can cause T cell exhaustion. This review also summarizes the recent progress in mechanisms underlying the tonic signaling and strategies to fine-tune the CAR tonic signaling. By understanding and precisely modulating tonic signaling, the efficacy of CAR-T therapies can be further optimized, offering new avenues for treatment across a broader spectrum of diseases. These findings have implications beyond CAR-T cells, potentially impacting other engineered immune cell therapies such as CAR-NK and CAR-M.
Humans ; Immunotherapy, Adoptive/methods* ; Receptors, Chimeric Antigen/immunology* ; Signal Transduction/immunology* ; T-Lymphocytes/immunology* ; Neoplasms/immunology* ; Animals

B lymphocytes (B cells) play a complex and paradoxical role in tumorigenesis. They can recognize tumor-associated antigens, present these antigens to T cells, and produce antibodies that directly target and eliminate tumor cells. This makes B cells a potentially powerful ally in combating cancer. However, B cells also exhibit immunosuppressive functions, secreting cytokines like IL-10 or generating tumor-promoting antibodies that dampen the anti-tumor immune response, and some tumor cells have even been shown to exploit B cells to promote their growth and metastasis. This dual nature of B cells presents both opportunities and challenges for tumor immunotherapy. In this review, we summarize the mechanisms underlying the multifaceted functions of B cells and their current applications in cancer immunotherapy. Furthermore, we also explore the key issues and future directions in this field, emphasizing the need for further research to fully harness the anti-tumor potential of B cells in the fight against cancer.
Humans ; B-Lymphocytes/immunology* ; Neoplasms/therapy* ; Carcinogenesis/immunology* ; Immunotherapy/methods* ; Animals

Therapeutic cancer vaccines have experienced a resurgence over the past ten years. Cancer vaccines are typically designed to enhance specific stages of the cancer-immunity cycle, primarily by activating the immune system to promote tumor regression and overcome immune resistance. In this review, we summarize the significant recent advancements in cancer immunotherapy based on the cancer-immunity cycle, including the effector cell function, infiltration, initiation, and exhaustion. We summarize the identification of tumor antigens and their delivery through cancer vaccines. We discuss how specific stages of the cancer-immunity cycle have been leveraged to augment anti-tumor immune responses and improve vaccine efficacy. Additionally, the impact of aging and myelosuppression, two prevalent forms of immunological stress, on the effectiveness of therapeutic cancer vaccines is deliberated. Finally, we summarize the current status of various therapeutic cancer vaccines at different clinical trial phases.
Humans ; Cancer Vaccines/therapeutic use* ; Neoplasms/therapy* ; Immunotherapy/methods* ; Antigens, Neoplasm/immunology* ; Animals

The introduction of PD-1 blockades to chemotherapy and radiotherapy has shown promising outcomes in patients with nasopharyngeal carcinoma, but anti-PD-1 therapies are only effective in a small proportion of patients, indicating the need for reliable predictive biomarkers of benefit from immunotherapy. Here, we summarized recent advances in immunotherapy for nasopharyngeal carcinoma and studies on potential predictors that correlated with treatment response or long-term survival after immunotherapy, including biomarkers in both the tumor microenvironment and the tumor macroenvironment. Some of these biomarkers have been validated as truly predictive of immunotherapy benefit using cohorts from randomized controlled trials, while others still require further validation of their predictive value. We also summarized the challenges and future directions of biomarker studies, hopefully facilitating the development of predictive biomarkers for immunotherapy that can eventually enter clinical practice.
Humans ; Tumor Microenvironment/immunology* ; Nasopharyngeal Carcinoma/immunology* ; Immunotherapy/methods* ; Nasopharyngeal Neoplasms/immunology* ; Biomarkers, Tumor/metabolism* ; Immune Checkpoint Inhibitors/therapeutic use*

Biliary tract cancer (BTC) is a rare group of malignancies that develop from the epithelial lining of the biliary tree and have a poor prognosis. Although chemotherapy is the standard of care for patients with advanced BTC in China, its clinical benefits are moderate. In recent years, the approval of targeted therapies and immunotherapies has provided new avenues for the management of advanced BTC. Nonetheless, the increasing number of personalized medicine approaches has created a challenge for clinicians choosing individualized treatment strategies based on tumor characteristics. In this article, we discuss recent progress in implementing precision medicine approaches for advanced BTC in China and examine genomic profiling studies in Chinese patients with advanced BTC. We also discuss the challenges and opportunities of using precision medicine approaches, as well as the importance of considering population-specific factors and tailoring treatment approaches to improve outcomes for patients with BTC. In addition to providing a comprehensive overview of current and emerging precision medicine approaches for the management of advanced BTC in China, this review article will support clinicians outside of China by serving as a reference regarding the role of patient- and population-specific factors in clinical decision-making for patients with this rare malignancy.
Humans ; Precision Medicine/methods* ; Biliary Tract Neoplasms/genetics* ; China ; Molecular Targeted Therapy ; Immunotherapy/methods*

Head and neck squamous cell carcinoma(HNSCC) associated with a poor prognosis and diminished quality of life for patients is the most prevalent pathological type among head and neck tumors. Currently,the standard treatment modalities comprise systemic therapies(including chemotherapy,targeted therapy,and immunotherapy) and local therapies(surgery and radiotherapy).Immunotherapy,characterized by high specificity and low toxicity,is progressively expanding from advanced palliative care to the stage of locally advanced curative treatment and has demonstrated promising efficacy.This review summarizes the latest advances in immunotherapy for HNSCC,aiming to provide reference for optimizing clinical management strategies and facilitating the clinical research.
Humans ; Immunotherapy/methods* ; Head and Neck Neoplasms/immunology* ; Squamous Cell Carcinoma of Head and Neck/therapy*

BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of subsequent radiotherapy (RT) following first-line treatment with durvalumab plus chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC). METHODS: A total of 122 patients with ES-SCLC from three hospitals during July 2019 to December 2021 were retrospectively analyzed. Inverse probability of treatment weighting (IPTW) analysis was performed to address potential confounding factors. The primary focus of our evaluation was to assess the impact of RT on progression-free survival (PFS) and overall survival (OS). RESULTS: After IPTW analysis, 49 patients received durvalumab plus platinum-etoposide (EP) chemotherapy followed by RT (Durva + EP + RT) and 72 patients received immunochemotherapy (Durva + EP). The median OS was 17.2 months vs . 12.3 months (hazard ratio [HR]: 0.38, 95% confidence interval [CI]: 0.17-0.85, P = 0.020), and the median PFS was 8.9 months vs . 5.9 months (HR: 0.56, 95% CI: 0.32-0.97, P = 0.030) in Durva + EP + RT and Durva + EP groups, respectively. Thoracic radiation therapy (TRT) resulted in longer OS (17.2 months vs . 14.7 months) and PFS (9.1 months vs . 7.2 months) compared to RT directed to other metastatic sites. Among patients with oligo-metastasis, RT also showed significant benefits, with a median OS of 17.4 months vs . 13.7 months and median PFS of 9.8 months vs . 5.9 months compared to no RT. Continuous durvalumab treatment beyond progression (TBP) prolonged OS compared to patients without TBP, in both the Durva + EP + RT (NA vs . 15.8 months, HR: 0.48, 95% CI: 0.14-1.63, P = 0.238) and Durva + EP groups (12.3 months vs . 4.3 months, HR: 0.29, 95% CI: 0.10-0.81, P = 0.018). Grade 3 or 4 adverse events occurred in 13 (26.5%) and 13 (18.1%) patients, respectively, in the two groups; pneumonitis was mostly low-grade. CONCLUSION Addition of RT after first-line immunochemotherapy significantly improved survival outcomes with manageable toxicity in ES-SCLC.
Humans ; Small Cell Lung Carcinoma/therapy* ; Retrospective Studies ; Male ; Female ; Middle Aged ; Lung Neoplasms/therapy* ; Aged ; Antibodies, Monoclonal/therapeutic use* ; Adult ; Immunotherapy/methods* ; Aged, 80 and over

Colorectal cancer (CRC), a major global health concern, necessitates innovative treatments. Chimeric antigen receptor (CAR) T cells have shown promises, yet they grapple with challenges. The spotlight pivots to the rising heroes: CAR natural killer (NK) cells, offering advantages such as higher safety profiles, cost-effectiveness, and efficacy against solid tumors. Nevertheless, the specific mechanisms underlying CAR NK cell trafficking and their interplay within the complex tumor microenvironment require further in-depth exploration. Herein, we provide insights into the design and engineering of CAR NK cells, antigen targets in CRC, and success in overcoming resistance mechanisms with an emphasis on the potential for clinical trials.
Colorectal Neoplasms/immunology* ; Humans ; Killer Cells, Natural/metabolism* ; Receptors, Chimeric Antigen/genetics* ; Immunotherapy, Adoptive/methods* ; Tumor Microenvironment/immunology* ; Animals

The remarkable efficacy of chimeric antigen receptor (CAR) T cell therapy in hematological malignancies has provided a solid basis for the therapeutic concept, wherein specific pathogenic cell populations can be eradicated by means of targeted recognition. During the past few years, CAR-based cell therapies have been extensively investigated in preclinical and clinical research across various non-tumor diseases, with particular emphasis in the treatment of autoimmune diseases (ADs), yielding significant advancements. The recent deployment of CD19-directed CAR T cells has induced long-lasting, drug-free remission in patients with systemic lupus erythematosus (SLE) and other systemic ADs, alongside a more profound immune reconstruction of B cell repertoire compared with conventional immunosuppressive agents and B cell-targeting biologics. Despite the initial success achieved by CAR T cell therapy, it is critical to acknowledge the divergences in its application between cancer and ADs. Through examining recent clinical studies and ongoing research, we highlight the transformative potential of this therapeutic approach in the treatment of SLE, while also addressing the challenges and future directions necessary to enhance the long-term efficacy and safety of CAR-based cell therapies in clinical practice.
Humans ; Lupus Erythematosus, Systemic/immunology* ; Receptors, Chimeric Antigen/metabolism* ; Immunotherapy, Adoptive/methods* ; Cell- and Tissue-Based Therapy/methods* ; Animals ; T-Lymphocytes/immunology*

BACKGROUND: Immune checkpoint inhibitors (ICIs) have been included in various neoadjuvant therapy (NAT) regimens for non-small cell lung cancer (NSCLC). However, due to the relatively short period for the use of ICIs in NAT, patients' clinical outcomes with different regimens are uncertain. Our study aims to examine the efficacy of neoadjuvant immunotherapy (NAIT) for NSCLC patients and compare the overall survival (OS) and event-free survival (EFS) of patients receiving different NAT regimens. METHODS: This study retrospectively included 308 NSCLC patients treated with different NAT regimens and subsequent surgery in National Cancer Center between August 1, 2016 and July 31, 2022. Kaplan-Meier survival analysis and Cox proportional hazards regression analysis were conducted to evaluate the prognosis of patients. RESULTS: With a median follow-up of 27.5 months, the 1-year OS rates were 98.8% and 96.2%, and the 2-year OS rates were 96.6% and 85.8% in patients of the NAIT and neoadjuvant chemotherapy (NACT) group, respectively (hazard ratio [HR], 0.339; 95% confidence interval [CI], 0.160-0.720; P = 0.003). The 1-year EFS rates were 96.0% and 88.0%, and the 2-year EFS rates were 92.0% and 77.7% for patients in the NAIT and NACT groups, respectively (HR, 0.438; 95% CI, 0.276-0.846; P = 0.010). For patients who did not achieve pathological complete response (pCR), significantly longer OS ( P = 0.012) and EFS ( P = 0.019) were observed in patients receiving NAIT than those receiving NACT. Different NAT regimens had little effect on surgery and the postoperative length of stay (6 [4, 7] days vs . 6 [4, 7] days, Z = -0.227, P = 0.820). CONCLUSIONS NAIT exhibited superior efficacy to NACT for NSCLC, resulting in longer OS and EFS. The OS and EFS benefits were also observed among patients in the NAIT group who did not achieve pCR.
Humans ; Carcinoma, Non-Small-Cell Lung/mortality* ; Male ; Female ; Lung Neoplasms/mortality* ; Middle Aged ; Immune Checkpoint Inhibitors/therapeutic use* ; Neoadjuvant Therapy/methods* ; Retrospective Studies ; Aged ; Adult ; Kaplan-Meier Estimate ; Treatment Outcome ; Immunotherapy/methods*