Therapeutic potential of interleukin-21 in cancer.

Interleukin-21 (IL-21) is an immunostimulatory cytokine which belongs to the common gamma-chain family of cytokines. It plays an import role in the development, differentiation, proliferation, and activation of immune cells, in particular T and natural killer (NK) cells. Since its discovery in 2000, IL-21 has been shown to regulate both adaptive and immune responses associates with key role in antiviral and antitumor responses. Recent advances indicate IL-21 as a promising target for cancer treatment and encouraging results were obtained in preclinical studies which investigated the potency of IL-21 alone or in combination with other therapies, including monoclonal antibodies, checkpoint inhibitory molecules, oncolytic virotherapy, and adoptive cell transfer. Furthermore, IL-21 showed antitumor effects in the treatment of patients with advanced cancer, with minimal side effects in several clinical trials. In the present review, we will outline the recent progress in IL-21 research, highlighting the potential of IL-21 based therapy as single agent or in combination with other drugs to enhance cancer treatment efficiency.

Interleukin-21 as an adjuvant in cancer immunotherapy: Current advances and future directions.

Immunotherapy has revolutionized cancer treatment. However, it's well-recognized that a considerable proportion of patients fail to benefit from immunotherapy, and to improve immunotherapy response is clinically urgent. Insufficient immune infiltration and immunosuppressive tumor microenvironments (TME) are main contributors to immunotherapy resistance. Thus sustaining functional self-renewal capacity for immune cells and subverting immune-suppressive signals are potential strategies for boosting the efficacy of immunotherapy. Interleukin-21 (IL-21), a crucial cytokine, which could enhance cytotoxic function of immune cells and reduces immunosuppressive cells enrichment in TME, shows promising orientations as an immunoadjuvant in tumor immunotherapy. This review focuses on IL-21 in cancer treatment, including function and mechanisms of IL-21, preclinical and clinical studies, and future directions for IL-21-assisted therapies.

Spesolimab, A Novel Interleukin-36 Inhibitor for Generalized Pustular Psoriasis Flares in Adult Patients.

Generalized pustular psoriasis (GPP) is a rare, immune-mediated inflammatory disease with characteristic cutaneous and systemic manifestations. Mutations in the interleukin-36 receptor antagonist (IL36RN) gene have been implicated in its pathogenesis. Spesolimab is a novel systemic biologic therapy that selectively inhibits interleukin-36. It was recently approved by Health Canada and the US FDA for the treatment of GPP flares in adults. Results from phase 1 and 2 studies have been promising. Herein, we review the efficacy and safety of spesolimab for the treatment of GPP flares, as demonstrated in clinical trials.

Clinical advances in biological therapy for generalized pustular psoriasis: a review.

INTRODUCTION: In 2022, U.S. Food and Drug Administration (FDA) approved the first biologics, intravenous spesolimab, for acute flare of generalized pustular psoriasis (GPP). The drug works by blocking IL-36 signaling, the key pathway of GPP. Among the known mutations causing GPP, IL36RN mutations are most common, and the presence of IL36RN mutations had been found to affect the clinical manifestations and treatment response of GPP. AREAS COVERED: Literature search was conducted in PubMed, Embase and ClinicalTrials.gov for relevant studies discussing biologic treatment for GPP with special emphasis on larger studies, pediatric group, pregnant women, and the influence of IL36RN mutation on the effectiveness of biologics. EXPERT OPINION: The approval of spesolimab for GPP flare treatment marks a new era. However, whether spesolimab will be placed as the treatment of choice remains unknown, considering its higher cost, lack of direct comparison with existing biologics, and uncertain effects on co-existing plaque-type psoriasis. However, the demonstration of numerically better efficacy for patients carrying pathogenic IL36RN mutations suggests the role of pharmacogenetics in the choices of GPP treatment. Future randomized studies are warranted to investigate the effectiveness and safety of biologics for GPP in pediatric and pregnant groups.

Biological effects of IL-21 on immune cells and its potential for cancer treatment.

Interleukin-21 (IL-21), a member of the IL-2 cytokine family, is one of the most important effector and messenger molecules in the immune system. Produced by various immune cells, IL-21 has pleiotropic effects on innate and adaptive immune responses via regulation of natural killer, T, and B cells. An anti-tumor role of IL-21 has also been reported in the literature, as it may support cell proliferation or on the contrary induce growth arrest or apoptosis of the tumor cell. Anti-tumor effect of IL-21 enhances when combined with other agents that target tumor cells, immune regulatory circuits, or other immune-enhancing molecules. Therefore, understanding the biology of IL-21 in the tumor microenvironment (TME) and reducing its systemic toxic and side effects is crucial to ensure the maximum benefits of anti-tumor treatment strategies. In this review, we provide a comprehensive overview on the biological functions, roles in tumors, and the recent advances in preclinical and clinical research of IL-21 in tumor immunotherapy.

Inflammatory mediators, oxidative stress and genetic disturbance in rheumatoid arthritis rats supported by alfalfa seeds metabolomic constituents via blocking interleukin-1receptor.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by aggressive cartilage and bone erosion. This work aimed to evaluate the metabolomic profile of Medicago sativa L. (MS) (alfalfa) seeds and explore its therapeutic impact against RA in rats. Arthritis was induced by complete Freund's adjuvant (CFA) and its severity was assessed by the arthritis index. Treatment with MS seeds butanol fraction and interlukin-1 receptor antagonist (IL-1RA) were evaluated through measuring interlukin-1 receptor (IL-1R) type 1 gene expression, interlukin-1 beta (IL-1ß), oxidative stress markers, C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), prostaglandin E2 (PGE2), caspase-3 (Cas-3), intracellular adhesion molecule-1 (ICAM-1), DNA fragmentation, and chromosomal damage. Total phenolics/ flavonoids content in the ethyl acetate, butanol fraction and crude extract of MS seeds were estimated. The major identified compounds were Quercetin, Trans-taxifolin, Gallic acid, 7,4'-Dihydroxyflavone, Cinnamic acid, Kudzusaponin SA4, Isorhamnetin 3-O-beta-D-2'',3'',4''-triacetylglucopyranoside, Apigenin, 5,7,4'-Trihydroxy-3'-methoxyflavone, Desmethylxanthohumol, Pantothenic acid, Soyasapogenol E, Malvidin, Helilandin B, Stigmasterol, and Wairol. Treatment with MS seeds butanol fraction and IL-1RA enhanced all the biochemical parameters and the histopathological features of the ankle joint. In conclusion, Trans-taxifolin was isolated for the first time from the genus Medicago. MS butanol fraction seeds extract and IL-1 RA were considered as anti-rheumatic agents.

Divergent neuroimmune signatures in the cerebrospinal fluid predict differential gender-specific survival among patients with HIV-associated cryptococcal meningitis.

Introduction: Survival among people with HIV-associated cryptococcal meningitis (CM) remains low, particularly among women, despite the currently optimal use of antifungal drugs. Cryptococcus dissemination into the central nervous system [brain, spinal cord, and cerebrospinal fluid (CSF)] elicits the local production of cytokines, chemokines, and other biomarkers. However, no consistent diagnostic or prognostic neuroimmune signature is reported to underpin the risk of death or to identify mechanisms to improve treatment and survival. We hypothesized that distinct neuroimmune signatures in the CSF would distinguish survivors from people who died on antifungal treatment and who may benefit from tailored therapy. Methods: We considered baseline clinical features, CSF cryptococcal fungal burden, and CSF neuroimmune signatures with survival at 18 weeks among 419 consenting adults by "gender" (168 women and 251 men by biological sex defined at birth). Results: Survival at 18 weeks was significantly lower among women than among men {47% vs. 59%, respectively; hazard ratio (HR) = 1.4 [95% confidence interval (CI), 1.0 to 1.9; p = 0.023]}. Unsupervised principal component analysis (PCA) demonstrated divergent neuroimmune signatures by gender, survival, and intragender-specific survival. Overall, women had lower levels of programmed death ligand 1, Interleukin (IL) (IL-11RA/IL-1F30, and IL-15 (IL-15) than men (all p < 0.028). Female survivors compared with those who died expressed significant elevations in levels of CCL11 and CXCL10 chemokines (both p = 0.001), as well as increased T helper 1, regulatory, and T helper 17 cytokines (all p < 0.041). In contrast, male survivors expressed lower levels of IL-15 and IL-8 compared with men who died (p < 0.044). Conclusions: Survivors of both genders demonstrated a significant increase in the levels of immune regulatory IL-10. In conclusion, the lower survival among women with CM was accompanied by distinct differential gender-specific neuroimmune signatures. These female and male intragender-specific survival-associated neuroimmune signatures provide potential targets for interventions to advance therapy to improve the low survival among people with HIV-associated CM.

Crosstalk: keratinocytes and immune cells in psoriasis.

In the past, psoriasis was considered a skin disease caused only by keratinocyte disorders. However, the efficacy of immunosuppressive drugs and biologics used to treat psoriasis proves that psoriasis is an immune-mediated disease. Indeed, a variety of immune cells are involved in the pathogenesis of psoriasis, including dendritic cells, Th17 cells, and resident memory T cells. Furthermore, keratinocytes play a role in the development of psoriasis as immune cells by secreting antibacterial peptides, chemokines, tumor necrosis factor-α, interleukin (IL)-36, and IL-23. These immune cells and skin cells interact and drive the aberrant differentiation and proliferation of keratinocytes. This crosstalk between keratinocytes and immune cells critical in the pathogenesis of psoriasis forms an inflammatory loop, resulting in the persistence or exacerbation of psoriasis plaques.

Clinical Efficacy of Bushen Yiqi Fuzheng Decoction Combined with Sunitinib in the Treatment of Postoperative Patients with Renal Cell Carcinoma and Its Influence on Their Immune Function.

BACKGROUND: This study aimed to investigate the effect of Bushen Yiqi Fuzheng decoction combined with sunitinib on the prognosis, clinical efficacy and immune function of patients with renal cell carcinoma (RCC) after surgery. METHODS: A total of 120 patients who experienced RCC after surgery were randomly divided into the observation and control groups in this prospective study, with 60 cases in each group. The therapeutic effect, improvement of clinical symptoms, changes of immune function-related indicators and adverse reactions during medication were recorded. The changes in immune cell population, midkine (MK), interleukin 35 (IL-35), hypoxia-inducible factor 2alpha (HIF-2α), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), carcinoembryonic antigen (CEA), osteopontin (OPN), ferritin (FERR) and beta2-microglobulin (ß2-MG) levels were measured. The Karnofsky performance status (KPS) score of patients was recorded. RESULTS: The total effective rate of the observation group (95%) was better than that of the control group (85%, p < 0.05). After treatment, the changes of immune function indexes in the control group were not obvious. The indexes related to immune function in the observation group significantly decreased. Significant differences were observed in the cluster of differentiation 3+ (CD3+), cluster of differentiation 4+ (CD4+), cluster of differentiation 8+ (CD8+) and CD4+/CD8+ between the two groups after treatment. The incidence of adverse reactions in the observation group was lower than that of the control group. The KPS of the observation group was higher than that of the control group. Before treatment, no differences were observed in the MK, IL-35, HIF-2α, CEA, OPN, FERR, ß2-MG, MMP-9 and TIMP-1 levels between the two groups. After treatment, the levels of the above parameters were lower than those before treatment, especially in the observation group. CONCLUSIONS: Bushen Yiqi Fuzheng decoction combined with sunitinib can significantly improve the clinical efficacy and postoperative immune function of RCC patients after surgery and down-regulate MMP-9 and TIMP-1 levels in the serum, which is beneficial to the prognosis of patients.

Cytokine polymorphisms and genotypic susceptibility of HCV infection in ribavirin response to peg interferon.

Immune responses are largely regulated by cytokines. Genetic polymorphisms of the regulatory coding regions are recognized to impact the expression of cytokines. The abnormal cytokine levels in hepatitis C virus (HCV) infection seems to be involved in disease progression, viral survival, and therapeutic response. The current study assesses the polymorphisms associated with IL-6, IL-10, IL28B, IFN-γ, TGF-ß, and TNF-α on the genotypic susceptibility to HCV infection and Ribavirin response to Peg interferon. Droplet digital polymerase chain reaction (PCR) was used to assess the gene polymorphisms associated with IL-6 A/G (rs2069837), IL-10-1082 G/A (rs1800896)], IL28B C/T (rs12979860), IFN-γ +874 A/T (rs2430561), TGF-ß 1-509 C/T (rs1800469) and TNF-α-308 G/A promoter (rs1800629) from stored samples of 200 healthy individuals and 300 HCV infected patients. There was a significant association of AG and AA genotypes of IL28B, IFN-γ, TGF-ß1, and TNF-α over HCV susceptibility and treatment outcome. However, no association between IL-6 and IL-10 gene polymorphism to HCV susceptibility response to the treatment. The observations indicate IL28B CT, TGF-ß1 CT, TT and TNF- AG with AA genotypes influence the cytokine expression, which is related to susceptibility and resistance to HCV infection and combined antiviral therapy.

Effects of Omalizumab on Serum Levels of Substance P, Calcitonin Gene-Related Peptide, Neuropeptide Y, and Interleukin-31 in Patients with Chronic Spontaneous Urticaria.

The mechanism of action of omalizumab in urticaria is still not literally known. This study examines the serum values of substance P (SP), calcitonin gene-related peptide (CGRP), neuropeptide Y (NPY), and interleukin-31 (IL-31) in patients using omalizumab. In this study, 30 patients with chronic spontaneous urticaria (CSU) who were going to be treated with omalizumab and 20 healthy volunteers took part. Demographic data, clinical data, and disease activity scores were noted. For serum SP, CGRP, NPY, and IL-31 values, 10 mL of blood were taken from the patients before starting the treatment, 3 months after the treatment, at the end of the 6th month, and from healthy volunteers all at once. The change in values measured at baseline, 3rd month, and 6th month was analyzed by the Friedman Test. The Mann-Whitney U test was used to compare the parameters obtained from the patients and control groups. The significance level was set at p=0.05. SP, CGRP, NPY, and IL-31 values were all statistically significantly lower in the CSU patient group compared to the control group. After treatment, the levels of SP and CGRP in the serum went up, and the levels of serum IL-31 went down. These changes were statistically significant. This study supports the view that omalizumab does not only affect IgE receptors but also affects mast cells through other mechanisms. According to our knowledge, this is the first study to show that omalizumab therapy and serum CGRP levels are related.

Advances in pathogenesis and treatment of ocular involvement in Behcet's disease.

Behcet's disease (BD) is a chronic multi-systemic disease characterized by relapsing-remitting oral ulcers, genital ulcers, ocular inflammatory involvements, and numerous other systemic features. Ocular involvements are quite common in BD and may cause severe tissue damage and potentially blindness. Even though the pathogenesis of BD remains ambiguous, growing evidences have shown that genetic factors, environmental triggers and immunological abnormalities play significant roles in its development and progression. Novel biotherapies targeting IFN-γ, TNF-α and interleukins have been used in recent years. In this review, we mainly pay attention to the ocular involvement of BD, and discuss the current understanding of mechanisms and advances in therapeutic approaches, especially novel biologics. Finally, we discuss the management in patients with pregnancy.

Analyzing the Antinociceptive Effect of Interleukin-31 in Mice.

The theory that an itch inhibits pain has been refuted; however, previous research did not investigate this theory for an interleukin-31 (IL-31)-induced itch. Previously, we have found that morphine-induced antinociception was partially reduced in IL-31 receptor A (IL-31RA)-deficient (IL-31RAKI) mice, indicating that IL-31RA may play an important role in morphine-induced peripheral antinociception. In the present study, we evaluated the effect of IL-31-induced analgesia on a 2,4,6-trinitrochlorobenzene (TNCB)-sensitized mice using a hot-plate test. This test evaluated the antinociceptive activity of morphine and non-steroidal anti-inflammatory drugs (NSAIDs). Repeated pretreatment with IL-31 showed significant antinociceptive action. Furthermore, its combination with morphine, but not with NSAIDs, increased the analgesic action. In contrast, treatment with TNCB and capsaicin decreased antinociception. Moreover, TNCB increased IL-31RA expression in the dorsal root ganglia at 24 h, whereas capsaicin inhibited it. The comparative action of several analgesics on TNCB or capsaicin was evaluated using a hot-plate test, which revealed that the antinociceptive activity was decreased or disappeared in response to capsaicin-induced pain in IL-31RAKI mice. These results indicate that the analgesic action of IL-31 involves the peripheral nervous system, which affects sensory nerves. These results provide a basis for developing novel analgesics using this mechanism.

Mechanisms of esophageal cancer metastasis and treatment progress.

Esophageal cancer is a prevalent tumor of the digestive tract worldwide. The detection rate of early-stage esophageal cancer is very low, and most patients are diagnosed with metastasis. Metastasis of esophageal cancer mainly includes direct diffusion metastasis, hematogenous metastasis, and lymphatic metastasis. This article reviews the metabolic process of esophageal cancer metastasis and the mechanisms by which M2 macrophages, CAF, regulatory T cells, and their released cytokines, including chemokines, interleukins, and growth factors, form an immune barrier to the anti-tumor immune response mediated by CD8+ T cells, impeding their ability to kill tumor cells during tumor immune escape. The effect of Ferroptosis on the metastasis of esophageal cancer is briefly mentioned. Moreover, the paper also summarizes common drugs and research directions in chemotherapy, immunotherapy, and targeted therapy for advanced metastatic esophageal cancer. This review aims to serve as a foundation for further investigations into the mechanism and management of esophageal cancer metastasis.

Pro- and Anti-Inflammatory Prostaglandins and Cytokines in Humans: A Mini Review.

Inflammation has been described for two millennia, but cellular aspects and the paradigm involving different mediators have been identified in the recent century. Two main groups of molecules, the prostaglandins (PG) and the cytokines, have been discovered and play a major role in inflammatory processes. The activation of prostaglandins PGE2, PGD2 and PGI2 results in prominent symptoms during cardiovascular and rheumatoid diseases. The balance between pro- and anti-inflammatory compounds is nowadays a challenge for more targeted therapeutic approaches. The first cytokine was described more than a century ago and is now a part of different families of cytokines (38 interleukins), including the IL-1 and IL-6 families and TNF and TGFß families. Cytokines can perform a dual role, being growth promotors or inhibitors and having pro- and anti-inflammatory properties. The complex interactions between cytokines, vascular cells and immune cells are responsible for dramatic conditions and lead to the concept of cytokine storm observed during sepsis, multi-organ failure and, recently, in some cases of COVID-19 infection. Cytokines such as interferon and hematopoietic growth factor have been used as therapy. Alternatively, the inhibition of cytokine functions has been largely developed using anti-interleukin or anti-TNF monoclonal antibodies in the treatment of sepsis or chronic inflammation.

IL-32 and its paradoxical role in neoplasia.

Interleukin-32 (IL-32) is an interleukin cytokine usually linked to inflammation. In recent years, it has been found that IL-32 exhibits both pro- and anti-tumor effects. Although most of those effects from IL-32 appear to favor tumor growth, some isoforms have shown to favor tumor suppression. This suggests that the role of IL-32 in neoplasia is very complex. Thus, the role of IL-32 in these various cancers and protein pathways makes it a very crucial component to consider when looking at potential therapeutic options in tumor treatment. In this review, we will explore what is currently known about IL-32, including its relationship with tumorigenesis and the potential for IL-32 to enhance local and systemic anti-tumor immune responses. Such a study might be helpful to accelerate the development of IL-32-based immunotherapies.

Interleukin-35 and Interleukin-37 anti-inflammatory effect on inflammatory bowel disease: Application of non-coding RNAs in IBD therapy.

Inflammatory bowel disease (IBD) is a widespread autoimmune disease that may even be life-threatening. IBD is divided into two major subtypes: ulcerative colitis and Crohn's disease. Interleukin (IL)-35 and IL-37 are anti-inflammatory cytokines that belong to IL-12 and IL-1 families, respectively. Their recruitment relieves inflammation in various autoimmune diseases, including psoriasis, multiple sclerosis, rheumatoid arthritis, and IBD. Regulatory T cells (Tregs) and regulatory B cells (Bregs) are the primary producers of IL-35/IL-37. IL-35 and IL-37 orchestrate the regulation of the immune system through two main strategies: Blocking nuclear transcription factor kappa-B (NF-kB) and mitogen-activated protein kinase (MAPK) signaling pathways or promoting the proliferation of Tregs and Bregs. Moreover, IL-35 and IL-37 can also inhibit inflammation by adjusting the T helper (Th)17/Treg ratio balance. Among the anti-inflammatory cytokines, IL-35 and IL-37 have significant potential to reduce intestinal inflammation. Therefore, administering IL-35/IL-37-based drugs or blocking their inhibitor microRNAs could be a promising approach to alleviate IBD symptoms. Overall, in this review article, we summarized the therapeutic application of IL-35 and IL-37 in both human and experimental models of IBD. Also, it is hoped that this practical information will reach beyond IBD therapy and shed some light on treating all intestinal inflammations.

Comparative study of Dapagliflozin versus Glimepiride effect on insulin regulated aminopeptidase (IRAP) and interleukin-34 (IL-34) in patient with type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is one of the most common diseases, that managed by several medications such as Glimepiride and Dapagliflozin. This study aims to compare the effects of Dapagliflozin versus Glimepiride on glycemic control, insulin resistance, and biomarkers as (extracellular domain of insulin regulated aminopeptidase) IRAPe, (interleukin-34) IL-34, and (N-terminal pro b-type natriuretic peptide) NT-proBNP. This study included 60 type 2 diabetic patients, who are randomized to receive either Glimepiride 4 mg/day (group 1) or Dapagliflozin 10 mg/day (group 2). Blood samples were collected at baseline and after 3 months of treatment for biochemical analysis. Additionally, HOMA-IR is calculated. After 3 months of receiving the intervention, there is no significant difference between the effects of Glimepiride and Dapagliflozin on FBG, PPBG, HbA1C%, fasting insulin, and HOMA-IR. The difference between both groups is significant for IL-34 (p = 0.002) and non-significant for IRAPe (p = 0.12) and NT-Pro BNP (p = 0.68). Both Glimepiride and Dapagliflozin significantly improve glycemic control, and HOMA-IR with no significant difference between them. Both drugs significantly improved the level of NT-proBNP. Dapagliflozin has a borderline significant effect on IRAPe but not IL-34, and Glimepiride has significant effect on IL-34 but not IRAPe. Clinical Trial Registration: This trial was registered on clinicaltrial.gov (NCT04240171).

Targeting IL-36 in Inflammatory Skin Diseases.

Interleukin (IL)-36 cytokines are members of the IL-1 superfamily of cytokines. IL-36 cytokines are composed of three agonists (IL-36α, IL-36ß, and IL-36γ) and two antagonists (IL-36 receptor antagonist [IL36Ra] and IL-38). These work in innate and acquired immunity and are known to contribute to host defense and to the pathogenesis of autoinflammatory diseases, autoimmune diseases, and infectious diseases. In the skin, IL-36α and IL-36γ are mainly expressed by keratinocytes in the epidermis, although they are also produced by dendritic cells, macrophages, endothelial cells, and dermal fibroblasts. IL-36 cytokines participate in the first-line defense of the skin against various exogenous assaults. IL-36 cytokines play significant roles in the host defense system and in the regulation of inflammatory pathways in the skin, collaborating with other cytokines/chemokines and immune-related molecules. Thus, numerous studies have shown IL-36 cytokines to play important roles in the pathogenesis of various skin diseases. In this context, the clinical efficacy and safety profiles of anti-IL-36 agents such as spesolimab and imsidolimab have been evaluated in patients with generalized pustular psoriasis, palmoplantar pustulosis, hidradenitis suppurativa, acne/acneiform eruptions, ichthyoses, and atopic dermatitis. This article comprehensively summarizes the roles played by IL-36 cytokines in the pathogenesis and pathophysiology of various skin diseases and summarizes the current state of research on therapeutic agents that target IL-36 cytokine pathways.

Interleukin-34 cancels anti-tumor immunity by PARP inhibitor.

OBJECTIVE: Breast cancer susceptibility gene 1 (BRCA1)-associated ovarian cancer patients have been treated with A poly (ADP-ribose) polymerase (PARP) inhibitor, extending the progression-free survival; however, they finally acquire therapeutic resistance. Interleukin (IL)-34 has been reported as a poor prognostic factor in several cancers, including ovarian cancer, and it contributes to the therapeutic resistance of chemotherapies. IL-34 may affect the therapeutic effect of PARP inhibitor through the regulation of tumor microenvironment (TME). METHODS: In this study, The Cancer Genome Atlas (TCGA) data set was used to evaluate the prognosis of IL-34 and human ovarian serous carcinoma. We also used CRISPR-Cas9 genome editing technology in a mouse model to evaluate the efficacy of PARP inhibitor therapy in the presence or absence of IL-34. RESULTS: We found that IL34 was an independent poor prognostic factor in ovarian serous carcinoma, and its high expression significantly shortens overall survival. Furthermore, in BRCA1-associated ovarian cancer, PARP inhibitor therapy contributes to anti-tumor immunity via the XCR1+ DC-CD8+ T cell axis, however, it is canceled by the presence of IL-34. CONCLUSION: These results suggest that tumor-derived IL-34 benefits tumors by creating an immunosuppressive TME and conferring PARP inhibitor therapeutic resistance. Thus, we showed the pathological effect of IL-34 and the need for it as a therapeutic target in ovarian cancer.