Therapeutic potential of targeting Nrf2 by panobinostat in pituitary neuroendocrine tumors.

We aimed to identify the druggable cell-intrinsic vulnerabilities and target-based drug therapies for PitNETs using the high-throughput drug screening (HTS) and genomic sequencing methods. We examined 9 patient-derived PitNET primary cells in HTS. Based on the screening results, the potential target genes were analyzed with genomic sequencing from a total of 180 PitNETs. We identified and verified one of the most potentially effective drugs, which targeted the Histone deacetylases (HDACs) both in in vitro and in vivo PitNET models. Further RNA sequencing revealed underlying molecular mechanisms following treatment with the representative HDACs inhibitor, Panobinostat. The HTS generated a total of 20,736 single-agent dose responses which were enriched among multiple inhibitors for various oncogenic targets, including HDACs, PI3K, mTOR, and proteasome. Among these drugs, HDAC inhibitors (HDACIs) were, on average, the most potent drug class. Further studies using in vitro, in vivo, and isolated PitNET primary cell models validated HDACIs, especially Panobinostat, as a promising therapeutic agent. Transcriptional surveys revealed substantial alterations to the Nrf2 signaling following Panobinostat treatment. Moreover, Nrf2 is highly expressed in PitNETs. The combination of Panobinostat and Nrf2 inhibitor ML385 had a synergistic effect on PitNET suppression. The current study revealed a class of effective anti-PitNET drugs, HDACIs, based on the HTS and genomic sequencing. One of the representative compounds, Panobinostat, may be a potential drug for PitNET treatment via Nrf2-mediated redox modulation. Combination of Panobinostat and ML385 further enhance the effectiveness for PitNET treatment.

Single-cell transcriptomics reveal distinct immune-infiltrating phenotypes and macrophage-tumor interaction axes among different lineages of pituitary neuroendocrine tumors.

BACKGROUND: Pituitary neuroendocrine tumors (PitNETs) are common gland neoplasms demonstrating distinctive transcription factors. Although the role of immune cells in PitNETs has been widely recognized, the precise immunological environment and its control over tumor cells are poorly understood. METHODS: The heterogeneity, spatial distribution, and clinical significance of macrophages in PitNETs were analyzed using single-cell RNA sequencing (scRNA-seq), bulk RNA-seq, spatial transcriptomics, immunohistochemistry, and multiplexed quantitative immunofluorescence (QIF). Cell viability, cell apoptosis assays, and in vivo subcutaneous xenograft experiments have confirmed that INHBA-ACVR1B influences the process of tumor cell apoptosis. RESULTS: The present study evaluated scRNA-seq data from 23 PitNET samples categorized into 3 primary lineages. The objective was to explore the diversity of tumors and the composition of immune cells across these lineages. Analyzed data from scRNA-seq and 365 bulk RNA sequencing samples conducted in-house revealed the presence of three unique subtypes of tumor immune microenvironment (TIME) in PitNETs. These subtypes were characterized by varying levels of immune infiltration, ranging from low to intermediate to high. In addition, the NR5A1 lineage is primarily associated with the subtype characterized by limited infiltration of immune cells. Tumor-associated macrophages (TAMs) expressing CX3CR1+, C1Q+, and GPNMB+ showed enhanced contact with tumor cells expressing NR5A1 + , TBX19+, and POU1F1+, respectively. This emphasizes the distinct interaction axes between TAMs and tumor cells based on their lineage. Moreover, the connection between CX3CR1+ macrophages and tumor cells via INHBA-ACVR1B regulates tumor cell apoptosis. CONCLUSIONS: In summary, the different subtypes of TIME and the interaction between TAM and tumor cells offer valuable insights into the control of TIME that affects the development of PitNET. These findings can be utilized as prospective targets for therapeutic interventions.

Alternations of Blood Pressure Following Surgical or Drug Therapy for Prolactinomas.

Several subtypes of pituitary neuroendocrine tumors (PitNETs), such as acromegaly and Cushing's disease, can result in hypertension. However, whether prolactinoma is associated with this complication remains unknown. Moreover, the effect of treatment with surgery or drugs on blood pressure (BP) is unknown. Herein, a retrospective study reviewed 162 patients with prolactinoma who underwent transsphenoidal surgery between January 2005 and December 2022. BP measurements were performed 1 day before and 5 days after surgery. Accordingly, patients' medical characteristics were recorded. In addition, in situ rat and xenograft nude-mice prolactinoma models have been used to mimic prolactinoma. In vivo BP and serum prolactin (PRL) levels were measured after cabergoline (CAB) administration in both rats and mice. Our data suggest that surgery can effectively decrease BP in prolactinoma patients with or without hypertension. The BP-lowering effect was significantly associated with several variables, including age, sex, disease duration, tumor size, invasion, dopamine agonists (DAs)-resistance, recurrence, and preoperative PRL levels. Moreover, in situ and xenograft prolactinomas induced BP elevation, which was alleviated by CAB treatment without and with a statistical difference in rats and mice, respectively. Thus, surgery or CAB can decrease BP in prolactinoma, indicating that pre- and postoperative BP management becomes essential.

Fully endoscopic far-lateral supracerebellar infratentorial approach for trigeminal neuralgia: illustrative case reports.

BACKGROUND: Trigeminal neuralgia (TN) is a common cause of craniofacial pain. The retrosigmoid approach is usually used to treat TN, but no cases of endoscopic far-lateral supracerebellar infratentorial approach (EF-SCITA) were used to undergo operation for TN. CASE PRESENTATION: Two patients were presented with severe facial pain and preliminary diagnosis was TN. Preoperative magnetic resonance imaging revealed that a superior cerebellar artery (SCA) compressed the trigeminal nerve in case 1, and a tumor located in the petrous apex extending into the Meckel's cave compressed the trigeminal nerve in case 2. Operations were achieved through the EF-SCITA. The pain was totally relieved with no postsurgical complications in both cases. CONCLUSIONS: We present the first two case reports of EF-SCITA to relieve classical and secondary TN successfully. The EF-SCITA can be a promising approach for treating TN.

Alleviating CB2-Dependent ER Stress and Mitochondrial Dysfunction Improves Chronic Cerebral Hypoperfusion-Induced Cognitive Impairment.

Augmentation of endoplasmic reticulum (ER) stress may trigger excessive oxidative stress, which induces mitochondrial dysfunction. The fatty acid amide hydrolase inhibitor, URB597, shows anti-oxidation characteristics in multiple neurological disorders. The present study aimed to determine whether inhibition of ER stress was involved in the protective effects of URB597 against chronic cerebral hypoperfusion (CCH)-induced cognitive impairment. Hippocampal HT-22 cells were exposed to oxygen-glucose deprivation. The cell viability, apoptosis, ER stress, mitochondrial ATP, and oxidative stress levels were assessed following treatment with URB597, benzenebutyric acid (4-PBA), and thapsigargin (TG). Furthermore, the effects of URB597 on ER stress and related pathways were investigated in the CCH animal model, including Morris water maze testing of cognition, western blotting analysis of ER stress signaling, and transmission electron microscopy of mitochondrial and ER ultrastructure changes. The results suggested that cerebral ischemia caused ER stress with upregulation of ER stress signaling-related proteins, mitochondrial dysfunction, neuronal apoptosis, ultrastructural injuries of mitochondria-associated ER membranes, and cognitive decline. Co-immunoprecipitation experiments confirmed the interaction between CB2 and ß-Arrestin1. Inhibiting ER stress by URB597 improved these changes by activating CB2/ß-Arrestin1 signaling, which was reversed by the CB2 antagonist, AM630. Together, the results identified a novel mechanism of URB597, involving CCH-induced cognitive impairment alleviation of CB2-dependent ER stress and mitochondrial dysfunction. Furthermore, this study identified CB2 as a potential target for therapy of ischemic cerebrovascular diseases.

Identification of the enhancer RNAs related to tumorgenesis of pituitary neuroendocrine tumors.

Background: Pituitary neuroendocrine tumors (PitNETs), which originate from the pituitary gland, account for 10%-15% of all intracranial neoplasms. Recent studies have indicated that enhancer RNAs (eRNAs) exert regulatory effects on tumor growth. However, the mechanisms underlying the eRNA-mediated tumorigenesis of PitNETs have not been elucidated. Methods: Normal pituitary and PitNETs tissues were used to identify the differentially expressed eRNAs (DEEs). Immune gene sets and hallmarks of cancer gene sets were quantified based on single sample gene set enrichment analysis (ssGSEA) algorithm using GSVA. The perspective of immune cells among all samples was calculated by the CIBERSORT algorithm. Moreover, the regulatory network composed of key DEEs, target genes of eRNAs, hallmarks of cancer gene sets, differentially expressed TF, immune cells and immune gene sets were constructed by Pearson correlation analysis. Small molecular anti-PitNETs drugs were explored by CMap analysis and the accuracy of the study was verified by in vitro and in vivo experiments, ATAC-seq and ChIP-seq. Results: In this study, data of 134 PitNETs and 107 non-tumorous pituitary samples were retrieved from a public database to identify differentially expressed genes. In total, 1128 differentially expressed eRNAs (DEEs) (494 upregulated eRNAs and 634 downregulated eRNAs) were identified. Next, the correlation of DEEs with cancer-related and immune-related gene signatures was examined to establish a co-expression regulatory network comprising 18 DEEs, 50 potential target genes of DEEs, 5 cancer hallmark gene sets, 2 differentially expressed transcription factors, 4 immune cell types, and 4 immune gene sets. Based on this network, the following four therapeutics for PitNETs were identified using Connectivity Map analysis: ciclopirox, bepridil, clomipramine, and alexidine. The growth-inhibitory effects of these therapeutics were validated using in vitro experiments. Ciclopirox exerted potential growth-inhibitory effects on PitNETs. Among the DEEs, GNLY, HOXB7, MRPL33, PRDM16, TCF7, and ZNF26 were determined to be potential diagnostic and therapeutic biomarkers for PitNETs. Conclusion: This study illustrated the significant influence of eRNAs on the occurrence and development of PitNETs. By constructing the co-expression regulation network, GNLY, HOXB6, MRPL33, PRDM16, TCF7, and ZNF26 were identified as relatively significant DEEs which were considered as the novel biomarkers of diagnosis and treatment of PitNETs. This study demonstrated the roles of eRNAs in the occurrence and development of PitNETs and revealed that ciclopirox was a potential therapeutic for pituitary adenomas.

A systematic survey of LU domain-containing proteins reveals a novel human gene, LY6A, which encodes the candidate ortholog of mouse Ly-6A/Sca-1 and is aberrantly expressed in pituitary tumors.

The Ly-6 and uPAR (LU) domain-containing proteins represent a large family of cell-surface markers. In particular, mouse Ly-6A/Sca-1 is a widely used marker for various stem cells; however, its human ortholog is missing. In this study, based on a systematic survey and comparative genomic study of mouse and human LU domain-containing proteins, we identified a previously unannotated human gene encoding the candidate ortholog of mouse Ly-6A/Sca-1. This gene, hereby named LY6A, reversely overlaps with a lncRNA gene in the majority of exonic sequences. We found that LY6A is aberrantly expressed in pituitary tumors, but not in normal pituitary tissues, and may contribute to tumorigenesis. Similar to mouse Ly-6A/Sca-1, human LY6A is also upregulated by interferon, suggesting a conserved transcriptional regulatory mechanism between humans and mice. We cloned the full-length LY6A cDNA, whose encoded protein sequence, domain architecture, and exon-intron structures are all well conserved with mouse Ly-6A/Sca-1. Ectopic expression of the LY6A protein in cells demonstrates that it acts the same as mouse Ly-6A/Sca-1 in their processing and glycosylphosphatidylinositol anchoring to the cell membrane. Collectively, these studies unveil a novel human gene encoding a candidate biomarker and provide an interesting model gene for studying gene regulatory and evolutionary mechanisms.

Mitochondrial Inhibitor Rotenone Triggers and Enhances Neuronal Ferroptosis Following Intracerebral Hemorrhage.

Ferroptosis, a form of regulatory non-apoptotic cell death driven by iron-dependent lipid peroxidation, accounts for more than 80% of the total types of neuronal death in the acute phase of intracerebral hemorrhage (ICH). Mitochondria have essential roles in energy production, macromolecule synthesis, cellular metabolism, and cell death regulation. However, its role in ferroptosis remains unclear and somewhat controversial, especially in ICH. This study aimed to investigate whether damaged mitochondria could trigger and enhance neuronal ferroptosis in ICH. The isobaric tag for relative and absolute quantitation proteomics on human ICH samples suggested that ICH caused significant damage to the mitochondria, which presented ferroptosis-like morphology under electron microscopy. Subsequently, use of the mitochondrial special inhibitor Rotenone (Rot) to induce mitochondrial damage showed that it has significant dose-dependent toxicity on primary neurons. Single Rot administration markedly inhibited neuronal viability, promoted iron accumulation, increased malondialdehyde (MDA) contents, decreased total superoxide dismutase (SOD) activity, and downregulated ferroptosis-related proteins RPL8, COX-2, xCT, ASCL4, and GPX4 in primary neurons. Moreover, Rot enhanced these changes via hemin and autologous blood administration in primary neurons and mice, mimicking the in vitro and in vivo ICH models, respectively. Furthermore, Rot exacerbated the ICH-induced hemorrhagic volumes, brain edema, and neurological deficits in mice. Together, our data revealed that ICH induced significant mitochondrial dysfunction and that mitochondrial inhibitor Rot can trigger and enhance neuronal ferroptosis.

DRD2 expression based on 18F-fallypride PET/MR predicts the dopamine agonist resistance of prolactinomas: a pilot study.

PURPOSE: The dopamine agonists (DA) have been used widely to treat prolactinomas. However, it is difficult to predict whether the patient will be responsive to DA treatment. METHODS: We aimed to investigate whether the in vivo expression of DRD2 based on 18F-fallypride PET/MR could predict the therapeutic effect of DA on prolactinomas. Seven patients with prolactinomas completed 18F-fallypride PET/MR. Among them, three patients underwent surgery and further tumor immunohistochemistry. Imaging findings and immunohistochemical staining were compared with treatment outcomes. RESULTS: 18F-fallypride PET/MR was visually positive in 7 of 7 patients, and DRD2 target specificity could be confirmed by immunohistochemical staining. A significantly lower tracer standard uptake value (SUV) could be detected in the resistant patients (n = 3) than in the sensitive patients (n = 4; SUVmean, 4.67 ± 1.32 vs. 13.57 ± 2.42, p < 0.05). DRD2 expression determined by 18F-fallypride PET/MR corresponded with the DA treatment response. CONCLUSION: 18F-fallypride PET/MR may be a promising technique for predicting DA response in patients with prolactinoma.

Pseudocapsule and pseudocapsule-based extracapsular resection in pituitary neuroendocrine tumors.

Since Costello et al. proposed the concept of pseudocapsule of pituitary neuroendocrine tumors (PitNETs) in 1936, many studies have been published on its occurrence, development process, histopathology, and morphology. Pseudocapsule has been proposed as the anatomical interface between PitNETs and normal pituitary gland, therefore the so-called pseudocapsule-based extracapsular resection (ER) technique was developed as an extracapsular surgery method for PitNETs,which differs from the conventional intracapsular resection (IR). In recent years, ER has also been widely used in patients of different tumor types, sizes, and age groups, because the pseudocapsule can be identified more clearly under the endoscopy. Endoscopic transsphenoidal resection for PitNETs has become the preferred surgical method. We reviewed relevant literatures in the past 10 years, showing that ER could achieve better rate of gross total resection (GTR) and biochemical remission, and reduce tumor recurrence than IR, without increasing postoperative complications. Therefore, the pseudocapsule and ER should be valued by neurosurgeons and actively promoted clinically.

Hydroxychloroquine overcomes cabergoline resistance in a patient with Lactotroph Pituitary neuroendocrine tumor: a case report.

Objective: A 22-year-old man complaining erectile dysfunction underwent transsphenoidal surgery for a 2.7 cm sellar mass with total resection and was confirmed at pathology to have a lactotroph pituitary neuroendocrine tumor (PiNET). Postoperatively, the patient's PRL remained at high level and therefore accepted high-dose dopamine receptor agonist (DA) therapy. After over 3 months of bromocriptine (BRC) (15mg/day) and over 3 years of cabergoline (CAB) (3mg/week) therapy, the patient's prolactin (PRL) never achieved long-term normalization. He was diagnosed with DA-resistant lactotroph PitNET. Method: In this study, the patient was given hydroxychloroquine (HCQ) (200 mg/d) and CAB (3 mg/w) in combination for four months. His PRL level was tested by blood test every month. Results: Taking the combination therapy of HCQ and CAB, the patient's uncontrolled PRL level was normalized within one month and was maintained at the normal level thereafter. Pituitary magnetic resonance imaging (MRI) images with enhancement showed no recurrence. The patient also regained normal sexual function. Discussion: This is the first report on the combination of HCQ with CAB for the effective treatment of DA-resistant lactotroph pituitary neuroendocrine tumor in a patient, which might provide a novel treatment strategy for clinical management.

Sellar Glomus Tumor Misdiagnosed as Pituitary Adenoma: A Case Report and Review of the Literature.

Glomus tumor is a rare mesenchymal tumor with an organ-like structure. Sellar glomus tumors are extremely rare with only six reported cases in the literature. Because of the lack of special clinical manifestations and imaging features, the disorder may be easily misdiagnosed as other sellar tumors, especially pituitary adenomas. Here, the present study showed a case of a 69-year-old male with hypopituitarism who was preliminarily misdiagnosed as non-functional pituitary adenoma.

TRIM65 determines the fate of a novel subtype of pituitary neuroendocrine tumors via ubiquitination and degradation of TPIT.

BACKGROUND: Pituitary neuroendocrine tumors (PitNETs) are common intracranial tumors that are classified into seven histological subtypes, including lactotroph, somatotroph, corticotroph, thyrotroph, gonadotroph, null cell, and plurihormonal PitNETs. However, the molecular characteristics of these types of PitNETs are not completely clear. METHODS: A total of 180 consecutive cases of PitNETs were collected to perform RNA sequencing. All subtypes of PitNETs were distinguished by unsupervised clustering analysis. We investigated the regulation of TPIT by TRIM65 and its effects on ACTH production and secretion in ACTH-secreting pituitary cell lines, as well as in murine models using biochemical analyses, confocal microscopy, and luciferase reporter assays. RESULTS: A novel subtype of PitNETs derived from TPIT lineage cells was identified as with normal TPIT transcription but with lowered protein expression. Furthermore, for the first time, TRIM65 was identified as the E3 ubiquitin ligase of TPIT. Depending on the RING domain, TRIM65 ubiquitinated and degraded the TPIT protein at multiple Lys sites. In addition, TRIM65-mediated ubiquitination of TPIT inhibited POMC transcription and ACTH production to determine the fate of the novel subtype of PitNETs in vitro and in vivo. CONCLUSION: Our studies provided a novel classification of PitNETs and revealed that the TRIM65-TPIT complex controlled the fate of the novel subtype of PitNETs, which provides a potential therapy target for Cushing's disease.

ACT001 inhibits pituitary tumor growth by inducing autophagic cell death via MEK4/MAPK pathway.

ACT001, derived from traditional herbal medicine, is a novel compound with effective anticancer activity in clinical trials. However, little is known regarding its role in pituitary adenomas. Here, we demonstrated that ACT001 suppressed cell proliferation and induced cell death of pituitary tumor cells in vitro and in vivo. ACT001 was also effective in suppressing the growth of different subtypes of human pituitary adenomas. The cytotoxic mechanism ACT001 employed was mainly related to autophagic cell death (ACD), indicated by autophagosome formation and LC3-II accumulation. In addition, ACT001-mediated inhibitory effect decreased when either ATG7 was downregulated or cells were cotreated with autophagy inhibitor 3-methyladenine (3-MA). RNA-seq analysis showed that mitogen-activated protein kinase (MAPK) pathway was a putative target of ACT001. Specifically, ACT001 treatment promoted the phosphorylation of JNK and P38 by binding to mitogen-activated protein kinase kinase 4 (MEK4). Our study indicated that ACT001-induced ACD of pituitary tumor cells via activating JNK and P38 phosphorylation by binding with MEK4, and it might be a novel and effective anticancer drug for pituitary adenomas.

Tumor-Associated Macrophages: New Horizons for Pituitary Adenoma Researches.

Macrophages are one of the most common infiltrating immune cells and an essential component of tumor microenvironment. Macrophages and the soluble cytokines and chemokines produced play an important role in tumorigenesis, progression, invasion and metastasis in solid tumors. Despite the multiple studies in other solid tumors, there is little known about macrophages in pituitary adenomas. Recently, studies about pituitary adenoma-infiltrated macrophages have been emerging, including the immunohistochemical and immunophenotypic analysis of the pituitary adenomas and further studies into the mechanism of the crosstalk between macrophages and tumor cells in vivo and in vitro. These studies have offered us new insights into the polarization of macrophages and its role in tumorigenesis, progression and invasion of pituitary adenomas. This review describes the advances in the field of pituitary adenoma-infiltrated macrophages and the prospect of targeting macrophages as cancer therapy in pituitary adenoma.

Case Report: Temozolomide Treatment of Refractory Prolactinoma Resistant to Dopamine Agonists.

Therapeutic agents for refractory prolactinomas that are resistant to dopamine agonists (DAs) are troublesome, and surgery often only removes a large part of the tumor without complete remission. Among the various second-line treatment regimens, the treatment effect of the alkylating agent temozolomide (TMZ) is only effective for approximately half of patients; however, complete remission is rare. Here we report a patient with prolactinoma who was resistant to high-dose cabergoline (CAB) treatment, demonstrating a continuous increase in both the tumor volume and the prolactin (PRL) level. Given that this case is a refractory prolactinoma, the patient underwent two transsphenoidal approach (TSA) surgeries. The pathological analysis indicated that the Ki-67 index increased significantly from 3% to 30%, and the expression levels of DRD2 and MGMT were low. Finally, TMZ treatment was recommended. A total of six cycles of TMZ standard chemotherapy shrank the tumor volume and the tumor disappeared completely. During the 6-month follow-up period, the tumor did not relapse again, and the PRL level was also normal. RNA sequencing and DNA whole genome sequencing were performed on this prolactinoma specimen, revealing 16 possible gene mutations, including a missense mutation of the PABPC1 gene. Additionally, the copy number variation analysis results showed that several chromosomes had copy number gains compared to the matched peripheral blood sample. In this case, low expression of DRD2 and high proliferation led to resistance to CAB, whereas low MGMT expression contributed to sensitivity to TMZ treatment. The results of genome sequencing still need further investigation at the molecular level to explain the tumor aggressiveness and high sensitivity to TMZ.

A potential impact of SARS-CoV-2 on pituitary glands and pituitary neuroendocrine tumors.

INTRODUCTION: Angiotensin-converting enzyme 2 (ACE2) is the receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The effects of SARS-CoV-2 on normal pituitary glands function or pituitary neuroendocrine tumors (PitNETs) have not yet been elucidated. Thus, the present study aimed to investigate the potential risks of SARS-CoV-2 infection on the impairment of pituitary glands and the development of PitNETs. METHODS: PitNETs tissues were obtained from 114 patients, and normal pituitary gland tissues were obtained from the autopsy. The mRNA levels of ACE2 and angiotensin II receptor type 1 (AGTR1) were examined by quantitative real-time PCR. Immunohistochemical staining was performed for ACE2 in 69 PitNETs and 3 normal pituitary glands. The primary tumor cells and pituitary cell lines (MMQ, GH3 and AtT-20/D16v-F2) were treated with diminazene aceturate (DIZE), an ACE2 agonist, with various dose regimens. The pituitary hormones between 43 patients with SARS-CoV-2 infection were compared with 45 healthy controls. RESULTS: Pituitary glands and the majority of PitNET tissues showed low/negative ACE2 expression at both the mRNA and protein levels, while AGTR1 showed high expression in normal pituitary and corticotroph adenomas. ACE2 agonist increased the secretion of ACTH in AtT-20/D16v-F2 cells through downregulating AGTR1. The level of serum adrenocorticotropic hormone (ACTH) was significantly increased in COVID-19 patients compared to normal controls (p < 0.001), but was dramatically decreased in critical cases compared to non-critical patients (p = 0.003). CONCLUSIONS: This study revealed a potential impact of SARS-CoV-2 infection on corticotroph cells and adenomas.

Lactate-induced M2 polarization of tumor-associated macrophages promotes the invasion of pituitary adenoma by secreting CCL17.

Background: Lactate greatly contributes to the regulation of intracellular communication within the tumor microenvironment (TME). However, the role of lactate in pituitary adenoma (PA) invasion is unclear. In this study, we aimed to clarify the effects of lactate on the TME and the effects of TME on PA invasion. Methods: To explore the correlation between TME acidosis and tumor invasion, LDHA and LAMP2 expression levels were quantified in invasive (n = 32) and noninvasive (n = 32) PA samples. The correlation between immune cell infiltration and tumor invasion was evaluated in 64 PAs. Critical chemokine and key signaling pathway components were detected by qPCR, Western blotting, siRNA knockdown, and specific inhibitors. The functional consequences of CCR4 signaling inhibition were evaluated in vitro and in vivo. Results: Lactate was positively associated with PA invasion. Of the 64 PA tissues, invasive PAs were related to high infiltration of M2-like tumor-associated macrophages (TAMs) (P < 0.05). Moreover, lactate secreted from PA cells facilitated M2 polarization via the mTORC2 and ERK signaling pathways, while activated TAMs secreted CCL17 to promote PA invasion via the CCL17/CCR4/mTORC1 axis. According to univariate analysis of clinical data, high CCL17 expression was associated with larger tumor size (P = 0.0438), greater invasion (P = 0.0334), and higher susceptibility to postoperative recurrence (P = 0.0195) in human PAs. Conclusion: This study illustrates the dynamics between PA cells and immune TME in promoting PA invasion via M2 polarization. CCL17 levels in the TME are related to the PA invasiveness and clinical prognosis, and the CCL17/CCR4/mTOCR1 axis may serve as potential therapeutic targets for Pas.