Development of pharmacological immunoregulatory anti-cancer therapeutics: current mechanistic studies and clinical opportunities.

Immunotherapy represented by anti-PD-(L)1 and anti-CTLA-4 inhibitors has revolutionized cancer treatment, but challenges related to resistance and toxicity still remain. Due to the advancement of immuno-oncology, an increasing number of novel immunoregulatory targets and mechanisms are being revealed, with relevant therapies promising to improve clinical immunotherapy in the foreseeable future. Therefore, comprehending the larger picture is important. In this review, we analyze and summarize the current landscape of preclinical and translational mechanistic research, drug development, and clinical trials that brought about next-generation pharmacological immunoregulatory anti-cancer agents and drug candidates beyond classical immune checkpoint inhibitors. Along with further clarification of cancer immunobiology and advances in antibody engineering, agents targeting additional inhibitory immune checkpoints, including LAG-3, TIM-3, TIGIT, CD47, and B7 family members are becoming an important part of cancer immunotherapy research and discovery, as are structurally and functionally optimized novel anti-PD-(L)1 and anti-CTLA-4 agents and agonists of co-stimulatory molecules of T cells. Exemplified by bispecific T cell engagers, newly emerging bi-specific and multi-specific antibodies targeting immunoregulatory molecules can provide considerable clinical benefits. Next-generation agents also include immune epigenetic drugs and cytokine-based therapeutics. Cell therapies, cancer vaccines, and oncolytic viruses are not covered in this review. This comprehensive review might aid in further development and the fastest possible clinical adoption of effective immuno-oncology modalities for the benefit of patients.

FLASH radiotherapy: A new milestone in the field of cancer radiotherapy.

Radiotherapy plays a pivotal role in the control and eradication of tumors, but it can also induce radiation injury to surrounding normal tissues while targeting tumor cells. In recent years, FLASH-Radiotherapy (FLASH-RT) has emerged as a cutting-edge research focus in the field of radiation therapy. By delivering high radiation doses to the treatment target in an ultra-short time, FLASH-RT produces the FLASH effect, which reduces the toxicity to normal tissues while achieving comparable tumor control efficacy to conventional radiotherapy. This review provides a brief overview of the development history of FLASH-RT and its impact on tumor control. Additionally, it focuses on introducing the protective effects and molecular mechanisms of this technology on various normal tissues, as well as exploring its synergistic effects when combined with other tumor therapies. Importantly, this review discusses the challenges faced in translating FLASH-RT into clinical practice and outlines its promising future applications.

Low-dose radiation therapy mobilizes antitumor immunity: New findings and future perspectives.

Radiotherapy has unique immunostimulatory and immunosuppressive effects. Although high-dose radiotherapy has been found to have systemic antitumor effects, clinically significant abscopal effects were uncommon on the basis of irradiating single lesion. Low-dose radiation therapy (LDRT) emerges as a novel approach to enhance the antitumor immune response due to its role as a leverage to reshape the tumor immune microenvironment (TIME). In this article, from bench to bedside, we reviewed the possible immunomodulatory role of LDRT on TIME and systemic tumor immune environment, and outlined preclinical evidence and clinical application. We also discussed the current challenges when LDRT is used as a combination therapy, including the optimal dose, fraction, frequency, and combination of drugs. The advantage of low toxicity makes LDRT potential to be applied in multiple lesions to amplify antitumor immune response in polymetastatic disease, and its intersection with other disciplines might also make it a direction for radiotherapy-combined modalities.

Challenges and opportunities in rare cancer research in China.

Cancer is one of the major public health challenges in China. Rare cancers collectively account for a considerable proportion of all malignancies. The lack of awareness of rare cancers among healthcare professionals and the general public, the typically complex and delayed diagnosis, and limited access to clinical trials are key challenges. Recent years have witnessed an increase in funding for research related to rare cancers in China. In this review, we provide a comprehensive overview of rare cancers and summarize the status of research on rare cancers in China and overseas, including the trends of funding and publications. We also highlight the challenges and perspectives regarding rare cancers in China.

Involved-field irradiation or elective-nodal irradiation in neoadjuvant chemo-radiotherapy for locally-advanced esophageal cancer: comprehensive analysis for dosimetry, treatment-related complications, impact on lymphocyte, patterns of failure and survival.

Purpose: To compare the differences between involved-field irradiation (IFI) and elective nodal irradiation (ENI) in selecting the optimal target area for neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC). Materials and methods: We retrospectively analyzed 267 patients with LA-ESCC, of whom 165 underwent ENI and 102 underwent IFI. Dosimetry, treatment-related complications, pathological responses, recurrence/metastasis patterns, and survival were compared between the two groups. Results: The median follow-up duration was 27.9 months. The R0 resection rates in the IFI and ENI groups were 95.1% and 92.7%, respectively (p=0.441), while the pathological complete response (pCR) rates were 42.2% and 34.5%, respectively (p=0.12). The ENI group received higher radiation doses to the heart (HV30:23.9% vs. 18%, p=0.033) and lungs (LV30:7.7% vs. 4.9%, p<0.001) than the IFI group. Consequently, the ENI group showed a higher incidence of grade 2 or higher radiation pneumonitis (30.3% vs. 17.6%, p=0.004) and pericardial effusion (26.7% vs. 11.8%, p=0.021) than the IFI group. Post-operation fistulas were observed in 3 (2.9%) and 17 cases (10.3%) in the IFI and ENI groups, respectively (p=0.026). In the multivariate analysis, smoking, positive lymph node involvement (pN+), and anastomotic fistula were independent predictors of overall survival (OS). The pN+ patients exhibited a greater propensity for recurrence compared to pN- patients, especially in the first year of follow-up (6.67% vs. 0.56%, p=0.003). Conclusion: The ENI group had a higher incidence of radiation-induced adverse events compared to the IFI group, likely due to the higher radiation doses to normal tissues. Considering the similar disease-free survival (DFS) and OS rates in the two groups, IFI may be suitable for nCRT in patients with LA-ESCC, although further prospective studies are warranted.

Non-destructive detection and recognition of pesticide residue levels on cauliflowers using visible/near-infrared spectroscopy combined with chemometrics.

In this study, two prediction models were developed using visible/near-infrared (Vis/NIR) spectroscopy combined with partial least squares discriminant analysis (PLS-DA) and least squares support vector machine (LS-SVM) for the detection of pesticide residues of avermectin, dichlorvos, and chlorothalonil at different concentration levels on the surface of cauliflowers. Five samples of each of the three different types of pesticide were prepared at different concentrations and sprayed in groups on the surface of the corresponding cauliflower samples. Utilizing the spectral data collected in the Vis/NIR as input values, comparison and analysis of preprocessed spectral data, and regression coefficient (RC), successive projections algorithm (SPA), and competitive adaptive reweighted sampling (CARS) were used in turn to downscale the data to select the main feature wavelengths, and PLS-DA and LS-SVM models were built for comparison. The results showed that the RC-LS-SVM was the best discriminant model for detecting avermectin residues concentration on the surface of cauliflowers, with a prediction set discriminant accuracy of 98.33%. For detecting different concentrations of dichlorvos, the SPA-LS-SVM had the best predictive accuracy of 95%. The accuracy of the model based on CARS-PLS-DA to identify chlorothalonil at different concentration levels on cauliflower surfaces reached 93.33%. The results demonstrated that the Vis/NIR spectroscopy combined with chemometrics could quickly and effectively identify pesticide residues on cauliflower surfaces, affording a certain reference for the rapid recognition of different pesticide residue concentrations on cauliflower surfaces. PRACTICAL APPLICATION: Vis/NIR spectroscopy can detect the concentration levels of pesticide residues on the surface of cauliflowers and help food regulators quickly and non-destructively detect traces of pesticides in food, providing a guarantee for food safety. The technique also provides a basis for determining pesticide residue concentrations on the surface of other vegetables.

Safety and Tolerability of Low-Dose Radiation and Stereotactic Body Radiotherapy + Sintilimab for Treatment-Naïve Stage IV PD-L1+ Non-Small Cell Lung Cancer Patients.

PURPOSE: Low-dose radiotherapy (LDRT) may enhance the synergistic antitumor effect of combined immunotherapy and stereotactic body radiotherapy (SBRT). The safety and efficacy of this novel triple-combination therapy were evaluated for the first time as first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: This prospective phase I study enrolled 29 patients and included a dose-escalation and dose-expansion phase. Patients received SBRT [30 Gray (Gy)/3f] to small lesions and LDRT (2 Gy/1f, 4 Gy/2f, or 10 Gy/5f) to a large lesion concurrently, followed by sintilimab (a programmed death-1 inhibitor). The primary endpoint was safety and tolerability; secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: No dose-limiting toxicities were observed during the dose-escalation phase; 4 Gy/2f was the recommended LDRT dose. Median follow-up was 15.6 months. Treatment-related adverse events (TRAE) occurred in 96.6% (28/29) of patients [grade ≥ 3; 20.7% (6/29)]; 2 patients (6.9%) discontinued due to TRAEs. Seven patients experienced pneumonitis (grade 2, n = 6; grade 3, n = 1). Immune-related adverse events were noted in 58.6% (17/29) of patients. In patients with tumor assessment (n = 28), ORR and confirmed ORR were 60.7% and 57.1%, respectively. Median PFS was 8.6 months (95% confidence interval, 3.7-16.5), and median OS was not reached. Exploratory analyses suggested both expanded and newly emerging T-cell receptor clonotypes were associated with better PFS. CONCLUSIONS: The findings indicate that the novel SBRT + LDRT + sintilimab therapy is safe and promising in patients with programmed death ligand-1-positive, driver gene-negative primary metastatic NSCLC.

Immunotherapy for non-small cell lung cancer with EGFR or HER2 exon 20 insertion mutations: a real-world analysis.

Background: Due to less sensitivity to classic tyrosine kinase inhibitors, effective first-line treatment is limited in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER2) exon 20 insertion (ex20ins) mutations. Meanwhile, the impact of driver genes on the efficacy of PD-1 inhibitors is discrepant. Our study aimed to assess the clinical response to immunotherapy in NSCLC patients with EGFR or HER2 ex20ins mutations. In parallel, patients treated with chemotherapy but without immunotherapy were included as controls. Methods: We retrospectively reviewed patients harboring ex20ins mutations treated with immune checkpoint inhibitors (ICIs) and/or chemotherapy in the real world. The clinical response was assessed by progression-free survival (PFS) and the objective response rate (ORR). Propensity score matching (PSM) was performed to control for confounding factors between immunotherapy and chemotherapy. Results: Of 72 patients enrolled, 38 had been treated with one line of single-agent immunotherapy or combined therapy including immunotherapy, and 34 had received conventional chemotherapy without immunotherapy. Among patients treated with immunotherapy, the median PFS was 10.7 months [95% confidence interval (CI): 8.2-13.2 months] in the first-line setting, with an ORR of 50% (8/16). The median PFS was significantly longer in the first-line immunotherapy group than in the chemotherapy group (10.7 vs. 4.6 months, P<0.001). A trend of an increased ORR in patients who received ICIs was observed compared with chemotherapy, but there was no statistical difference (50% vs. 21.9%, P=0.096). After PSM, the median PFS with first-line immunotherapy was still longer than that with chemotherapy (10.7 vs. 4.6 months, P=0.028). Grade 3-4 adverse events (AEs) were observed in 13.2% (5/38) of patients, with the majority developing granulocytopenia (40%, 2/5). One patient discontinued treatment due to a grade 3 rash after three cycles of ICI plus anlotinib treatment. Conclusions: The results showed that immunotherapy combined with chemotherapy may play a role in the first-line treatment of NSCLC patients with ex20ins mutations. This finding requires further investigation for application.

Targeted therapy for rare lung cancers: Status, challenges, and prospects.

Lung cancer causes the most cancer-related deaths worldwide. In recent years, molecular and immunohistochemical techniques have rapidly developed, further inaugurating an era of personalized medicine for lung cancer. The rare subset of lung cancers accounts for approximately 10%, each displaying distinct clinical characteristics. Treatments for rare lung cancers are mainly based on evidence from common counterparts, which may lead to unsolid clinical benefits considering intertumoral heterogeneity. The increasing knowledge of molecular profiling of rare lung cancers has made targeting genetic alterations and immune checkpoints a powerful strategy. Additionally, cellular therapy has emerged as a promising way to target tumor cells. In this review, we first discuss the current status of targeted therapy and preclinical models for rare lung cancers, as well as provide mutational profiles by integrating the results of existing cohorts. Finally, we point out the challenges and future directions for developing targeted agents for rare lung cancer.

Ferroptosis, necroptosis, and pyroptosis in cancer: Crucial cell death types in radiotherapy and post-radiotherapy immune activation.

Tumor cell death and antitumor immune activation induced by radiotherapy are extensively well-studied. While radiotherapy is believed to mainly induce tumor cell necrosis and apoptosis, recent studies have shown that it can also induce ferroptosis, necroptosis, and pyroptosis in tumor cells. However, studies on the role of ferroptosis, necroptosis, and pyroptosis in radiotherapy and post-radiotherapy immune activation are limited. In this review, we summarize the comprehensive literature on the molecular mechanisms and more recent research progress related to radiotherapy-induced ferroptosis, necroptosis, and pyroptosis in tumor cells. Further, we discuss the role of tumor cells undergoing these types of cell death in immune activation after radiotherapy. In addition, we highlight some unresolved questions on the association of radiotherapy with ferroptosis, necroptosis, and pyroptosis. This review can improve our current understanding of the relationship between radiotherapy and different cell death pathways and provide a theoretical framework to improve the therapeutic effect of tumor radiotherapy in the future.

Photoallosteric Polymersomes toward On-Demand Drug Delivery and Multimodal Cancer Immunotherapy.

Allosteric transitions can modulate the self-assembly and biological function of proteins. It remains, however, tremendously challenging to design synthetic allosteric polymeric assemblies with spatiotemporally switchable hierarchical structures and functionalities. Here, a photoallosteric polymersome is constructed that undergoes a rapid conformational transition from ß-sheet to α-helix upon exposure to near-infrared light irradiation. In addition to improving nanoparticle cell penetration and lysosome escape, photoinduced allosteric behavior reconstructs the vesicular membrane structure, which stimulates the release of hydrophilic cytolytic peptide melittin and hydrophobic kinase inhibitor sorafenib. Combining on-demand delivery of multiple therapeutics with phototherapy results in apoptosis and immunogenic death of tumor cells, remold the immune microenvironment and achieve an excellent synergistic anticancer efficacy in vivo without tumor recurrence and metastasis. Such a light-modulated allosteric transition in non-photosensitive polymers provides new insight into the development of smart nanomaterials for biosensing and drug delivery applications.

Cu-Catalyzed Polychloromethylamination of Styrenes through C(sp3 )-H Bond Cleavage.

A copper-catalyzed three-component coupling reaction has been developed allowing the rapid building of valuable complex highly functionalized ß-polychloromethyl amines from simple styrenes, arylamines, and dichloromethane/chloroform. Using aryldiazonium salts as a radical initiator, a series of corresponding products are obtained with moderate to good yields under a carbon dioxide or nitrogen atmosphere (50 psi). In addition, good functional group tolerance can be observed.

Two-sided roles of adipose tissue: Rethinking the obesity paradox in various human diseases from a new perspective.

Overweight and obesity, as a result of excess fat accumulation, have become a worldwide public health issue. Recent studies have shown that obesity is closely related to many human diseases, such as cancer, cardiovascular diseases, and type 2 diabetes mellitus, in which adipose tissue plays a dual role. In addition to thermal and mechanical insulation and a critical role in energy storage and heat production, adipose tissue is also a highly plastic endocrine and signaling organ that secretes multiple bioactive molecules for inter-organ crosstalk. The phenotypic and biological changes of adipose tissue under pathological conditions, especially in obesity, increase the challenge of deciphering the positive or negative effects of adipose tissue in disease. Despite numerous studies on obesity and adipose tissue, the ambiguous role of adipose tissue on specific organs or tissues in different diseases is not fully understood, and the definite mechanisms remain obscure. In this review, we first summarize the basic biological characteristics of adipose tissue in the physiological state and the abnormal remodeling of adipose tissue during obesity. We then discuss the complex and disparate effects of obesity on various human diseases, with a particular focus on the dual roles and underlying mechanisms of adipose tissue, a quintessential player in obesity, in this process. More importantly, rethinking the causes of the "obesity paradox" phenomenon in diseases from the perspective of adipose homeostasis and dysfunction provides a novel strategy for disease treatment by intervening in fat function.

Psychological distress and eustress in cancer and cancer treatment: Advances and perspectives.

Facing cancer diagnosis, patients with cancer are prone to psychological stress and consequent psychological disorders. The association between psychological stress and cancer has long been a subject of high interest. To date, preclinical studies have gradually uncovered the promotive effects of psychological distress on tumor hallmarks. In contrast, eustress may exert suppressive effects on tumorigenesis and beneficial effects on tumor treatment, which brings a practicable means and psychosocial perspective to cancer treatment. However, the underlying mechanisms remain incompletely understood. Here, by focusing on the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, as well as stress-related crucial neurotransmitters and hormones, we highlight the effects of distress and eustress on tumorigenesis, the tumor microenvironment, and tumor treatment. We also discuss the findings of clinical studies on stress management in patients with cancer. Last, we summarize questions that remain to be addressed and provide suggestions for future research directions.

Leptomeningeal metastases in non-small cell lung cancer: Diagnosis and treatment.

Leptomeningeal metastasis (LM) is a rare complication of non-small cell lung cancer (NSCLC) with highly mortality. LM will occur once tumor cells spread to the cerebrospinal fluid (CSF) space. Patients may suffer blindness, paralysis, and mental disorders that seriously affect their quality of life. There is a clear unmet need to improve the efficacy of diagnosis and treatment of LM. To better solve this problem, it is helpful to clarify the potential mechanisms of LM. Clinical manifestations, magnetic resonance imaging, and CSF biopsy are the key components in the diagnosis of NSCLC with LM. CSF cytology is insufficient and should be combined with liquid biology. The application of radiotherapy, intrathecal treatment, targeted therapy and immunotherapy provides more options for LM patients. Each treatment has a particular level of efficacy and can be used alone or in combination for individual patients. New technologies in radiotherapy, drug repositioning in intrathecal treatment, and the higher CSF permeability in TKIs have brought new breakthroughs in the treatment of LM. This review focused on clarifying the potential mechanisms, discussing the major clinical challenges, and summarizing recent advances in the diagnosis and treatment of LM from NSCLC. Future research is essential to improve the efficiency of diagnosis, to optimize therapy and to enhance patient prognosis.

Surface Defect Detection of Fresh-Cut Cauliflowers Based on Convolutional Neural Network with Transfer Learning.

A fresh-cut cauliflower surface defect detection and classification model based on a convolutional neural network with transfer learning is proposed to address the low efficiency of the traditional manual detection of fresh-cut cauliflower surface defects. Four thousand, seven hundred and ninety images of fresh-cut cauliflower were collected in four categories including healthy, diseased, browning, and mildewed. In this study, the pre-trained MobileNet model was fine-tuned to improve training speed and accuracy. The model optimization was achieved by selecting the optimal combination of training hyper-parameters and adjusting the different number of frozen layers; the parameters downloaded from ImageNet were optimally integrated with the parameters trained on our own model. A comparison of test results was presented by combining VGG19, InceptionV3, and NASNetMobile. Experimental results showed that the MobileNet model's loss value was 0.033, its accuracy was 99.27%, and the F1 score was 99.24% on the test set when the learning rate was set as 0.001, dropout was set as 0.5, and the frozen layer was set as 80. This model had better capability and stronger robustness and was more suitable for the surface defect detection of fresh-cut cauliflower when compared with other models, and the experiment's results demonstrated the method's feasibility.

Immunotherapy for EGFR-mutant advanced non-small-cell lung cancer: Current status, possible mechanisms and application prospects.

Immune checkpoint inhibitors (ICIs) are effective against advanced and even perioperative non-small-cell lung cancer (NSCLC) and result in durable clinical benefit, regardless of programmed death ligand-1 (PD-L1) expression status in cancer. Existing clinical evidence shows that the effect of immunotherapy in patients with EGFR-mutant NSCLC after the development of tyrosine kinase inhibitor (TKI) resistance is not satisfactory. However, compared with monotherapy, ICIs combined with chemotherapy can improve the efficacy. Encouragingly, compared with that of patients with sensitive mutations, the progression-free survival of patients with rare mutations who were treated with ICIs was increased. Adequately maximizing the efficacy of ICIs in EGFR-mutant NSCLC patients is worth exploring. In this review, we described preclinical and clinical studies of ICIs or combined therapy for EGFR-mutant NSCLC. We further focused on EGFR mutations and the cancer immune response, with particular attention given to the role of EGFR activation in the cancer-immunity cycle. The mechanisms for the natural resistance to ICIs were explored to identify corresponding countermeasures that made more EGFR-mutant NSCLC patients benefit from ICIs.

Detection of Soluble Solids Content in Different Cultivated Fresh Jujubes Based on Variable Optimization and Model Update.

To solve the failure problem of the visible/near infrared (VIS/NIR) spectroscopy model, soluble solids content (SSC) detection for fresh jujubes cultivated in different modes was carried out based on the method of variable optimization and model update. Iteratively retained informative variables (IRIV) and successive projections algorithm (SPA) algorithms were used to extract characteristic wavelengths, and least square support vector machine (LS-SVM) was used to establish detection models. Compared with IRIV, IRIV-SPA achieved better performance. Combined with the offset properties of the wavelength, repeated wavelengths were removed, and wavelength recombination was carried out to create a new combination of variables. Using these fused wavelengths, the model was recalibrated based on the Euclidean distance between samples. The LS-SVM detection model of SSC was established using the update method of wavelength fusion-Euclidean distance. Good prediction results were achieved using the proposed model. The determination coefficient (R2), root mean square error (RMSE), and residual predictive deviation (RPD) of the test set on SSC of fresh jujubes cultivated in the open field were 0.82, 1.49%, and 2.18, respectively. The R2, RMSE, and RPD of the test set on SSC of fresh jujubes cultivated in the rain shelter were 0.81, 1.44%, and 2.17, respectively. This study realized the SSC detection of fresh jujubes with different cultivation and provided a method for the establishment of a robust VIS/NIR detection model for fruit quality, effectively addressing the industry need for identifying jujubes grown in the open field.

Exogenous Melatonin Treatment Induces Disease Resistance against Botrytis cinerea on Post-Harvest Grapes by Activating Defence Responses.

Botrytis cinerea seriously affects the value of post-harvest grapes. Melatonin can act as an exogenous regulator in the resistance of exogenous pathogens due to its antioxidant activity. An artificial inoculation trial was conducted to research the induced resistance mechanism of melatonin treatment using the table grape "Muscat Hamburg" (Vitis vinifera L. cv). Grapes were immersed with 0.02, 0.2, and 2 mmol/L melatonin, followed by B. cinerea suspension injections after 48 h. The results showed that the mycelial growth and spore germination of B. cinerea was not significantly inhibited by melatonin at different concentrations (0.02-2 mmol/L). However, post-harvest melatonin treatment inhibited the increase of disease incidence and severity of grey mould, induced the synthesis and accumulation of total phenols and flavonoids, reduced malondialdehyde generation, and inhibited an increase in cell membrane permeability. Meanwhile, defensive enzyme activities, including superoxide dismutase (SOD), peroxidize (POD), catalase (CAT), phenylalanine ammonia-lyase (PAL), polyphenol oxidase (PPO), chitinase (CHI), and ß-1,3-glucanase, were significantly increased in fruits treated with exogenous melatonin. These results suggested that exogenous melatonin treatment could activate defence responses to combat the infection of B. cinerea in post-harvest grapes.

PD-1 signaling facilitates activation of lymphoid tissue inducer cells by restraining fatty acid oxidation.

Anti-programmed death-1 (PD-1) immunotherapy that aims to restore T cell activity in cancer patients frequently leads to immune-related adverse events such as colitis. However, the underlying mechanism is still elusive. Here, we find that Pdcd1-deficient mice exhibit disrupted gut microbiota and aggravated dextran sulfate sodium (DSS)-induced colitis. In addition to T cells, PD-1 is also substantially expressed in colonic lymphoid tissue inducer (LTi) cells. During DSS-induced colitis, LTi cell activation is accompanied by increased PD-1 expression, whereas PD-1 deficiency results in reduced interleukin-22 (IL-22) production by LTi cells and exacerbated inflammation. Mechanistically, activated LTi cells reprogram their metabolism toward carbohydrate metabolism and fatty acid synthesis, while fatty acid oxidation (FAO) is unchanged. However, PD-1 deficiency leads to significantly elevated FAO in LTi cells, which in turn attenuates their activation and IL-22 production. Consistently, FAO suppression efficiently restores IL-22 production in Pdcd1-/- LTi cells. Thus, our study provides unforeseen mechanistic insight into colitis occurrence during anti-PD-1 immunotherapy through LTi cell metabolic reconfiguration.