The intricate interplay between natriuretic peptides and their receptors is emerging as a groundbreaking frontier in cancer biology, revealing layers of complexity that promise to transform therapeutic strategies. Traditionally celebrated for their vital roles in cardiovascular and renal homeostasis, the natriuretic peptide system has now been thrust into the spotlight for its paradoxical roles in tumorigenesis. These small but potent peptides — atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) — engage with distinct receptors (NPRA, NPRB, NPRC) to wield influence over cell proliferation, immune modulation, and tumor microenvironment remodeling, positioning them as potent, if double-edged, agents in cancer progression and suppression.
ANP, a 28-amino acid hormone synthesized predominantly by atrial cardiomyocytes, has been long studied for its cardiovascular benefits. However, emerging evidence exposes a dualistic nature when it comes to oncogenic processes. Binding primarily to the transmembrane guanylyl cyclase receptor NPRA, ANP catalyzes the conversion of GTP to cyclic GMP (cGMP), setting off downstream signaling cascades that intricately control cellular proliferation and gene expression. The ANP/NPRA axis exemplifies a yin-yang relationship with cancer, as it can drive tumor progression in certain contexts while inhibiting it in others, especially dependent on concentration gradients and cellular context. These nuanced roles underscore NPRA’s potential as both a biomarker and a therapeutic target for a broad spectrum of malignancies.
Delving deeper into the cellular dynamics, gastric cancer research has illustrated that gastric adenocarcinoma (AGS) cells express notably high levels of NPRA, while non-malignant gastric epithelial cells lack detectable receptor presence. Strikingly, low doses of ANP promote AGS cell growth via cGMP-mediated PKG signaling pathways involving ion channels such as KCNQ1. Conversely, higher concentrations of ANP inhibit proliferation through mechanisms independent of cGMP, hinting at sophisticated feedback loops and receptor modulatory effects. This concentration-dependent duality accentuates the need for refined dosage control in prospective therapeutic modalities targeting this axis.
Complementing ANP’s story, BNP, a 32-amino acid peptide secreted primarily by ventricular cardiomyocytes under stress, reveals a similarly complex portrait in oncology. BNP’s receptor interactions extend beyond NPRA to engage the clearance receptor NPRC, which lacks guanylyl cyclase activity but modulates critical G-protein signaling pathways. This dichotomy facilitates BNP’s regulation of proliferation and apoptosis through pathways such as ERK and PI3K/AKT, which are well-recognized oncogenic cascades. Clinically, elevated plasma NT-proBNP levels correlate with poor prognosis and advanced disease stages across various cancers, including lung, breast, and prostate, signaling BNP’s emerging role as a biomarker for systemic inflammation and tumor progression.
Yet, the therapeutic exploitation of BNP remains challenged by its short half-life, prompting the development of innovative hybrid molecules that enhance stability and bioavailability. These engineered conjugates embody the future of peptide-based cancer therapies, leveraging molecular design to sustain antitumor efficacy while minimizing systemic degradation.
Arguably the most promising candidate in the natriuretic peptide family is CNP, a 22-amino acid peptide whose expression predominates within vascular endothelial cells. CNP engages selectively with the NPRB receptor, a guanylyl cyclase with robust downstream cGMP signaling but minimal affinity for NPRA or NPRC. Its selective receptor engagement enables CNP to exquisitely modulate vascular homeostasis, immune cell infiltration, and tumor stroma remodeling with precision. Crucially, CNP-mediated activation of NPRB stabilizes endothelial junctions, reduces vascular leakiness, and enhances pericyte coverage, thereby normalizing the aberrant tumor vasculature characteristic of solid malignancies. This vascular normalization alleviates hypoxia-driven pathways and facilitates drug penetration, architecting a microenvironment conducive to effective therapy.
The introduction of stable CNP derivatives, particularly the diacylated form (dCNP), has overcome historical pharmacokinetic challenges posed by native CNP’s fleeting half-life. Preclinical trials showcase dCNP’s ability to double intratumoral chemotherapy accumulation, potentiate immune checkpoint blockade responses, and substantially increase CAR-T cell infiltration in solid tumors like glioblastoma. Impressively, in melanoma metastasis models, dCNP reduced lung nodules by 60%, underscoring its capacity to impede cancer dissemination without adversely affecting primary tumors.
The receptors of natriuretic peptides not only mediate direct effects on cancer cells but also profoundly rewire the tumor microenvironment (TME), the complex ecosystem where stromal, immune, and cancerous cells converge. NPRA emerges as a potent oncogene within this milieu, fostering pro-angiogenic states through upregulation of VEGF and CXCR4, thereby generating hypoxic, acidic niches favorable to tumor survival. NPRA’s influence extends into immune modulation, where its signaling curtails anti-tumor immunity by promoting regulatory T cells through dendritic cell reprogramming, orchestrating an immunosuppressive environment that facilitates immune escape.
Further investigations implicate NPRA-driven inflammation as a linchpin in cancer progression, with evidence showing that NPRA deficiency not only alleviates lung inflammation but also confers protection against skin and ovarian cancers in murine models. This multidimensional role situates NPRA signaling at the nexus of inflammation, angiogenesis, and immune regulation, positioning it as a compelling target for therapeutic disruption.
In contrast, NPRB activation by dCNP orchestrates a countermeasure within the TME, leading to vascular normalization and dampening of hypoxia-associated fibroblast activation and TGF-β signaling. This fosters increased pericyte coverage and enhances immune cell infiltration, including effector T cells, NK cells, and cross-presenting dendritic cells, while simultaneously reducing exhaustion markers such as PD-1 and TIM-3. These immunological recalibrations synergize with checkpoint inhibitors, tripling response rates in pancreatic ductal adenocarcinoma models, signaling a new horizon in combination immunotherapy.
NPRC’s role remains enigmatic yet pivotal, as it modulates natriuretic peptide bioavailability by scavenging these molecules and exhibits dual functions. In certain cancers like prostate and colorectal, NPRC facilitates tumor progression by limiting peptide availability, while in others, such as osteosarcoma, it paradoxically exerts oncogenic effects via PI3K/AKT pathway suppression. Importantly, NPRC-mediated reshaping of immune cell dynamics converts immunologically “cold” tumors into “hot” ones, characterized by enhanced cytotoxic lymphocyte infiltration and reduced suppressive cell populations, thereby increasing responsiveness to immunotherapies.
At the molecular crossroads, natriuretic peptides influence key oncogenic signaling networks. NPRA activation inhibits canonical pathways such as RAS-MAPK, Wnt/β-catenin, and STAT3, curbing cellular proliferation and angiogenesis. Notably, ANP downregulates β-catenin expression and Wnt pathway effectors like WNT3a and sFRP-3, resulting in attenuated tumor growth in pancreatic and colorectal models. Similarly, BNP’s activation of NPRA-PKG triggers the STAT3-Opa1 axis, enhancing mitochondrial fusion and reducing reactive oxygen species, which are known drivers of cancer metastasis.
The cross-talk extends to modulation of MAPK signaling, where ANP inhibits VEGF-stimulated JNK, ERK1/2, and p38 activity, diminishing vascular proliferation and tumor cell growth. Intriguingly, CNP activates ERK1/2-MAPK via NPRB independently of cGMP, influencing gene transcription that may impact pituitary tumorigenesis, indicating unique receptor-specific signaling nuances across tissue types and tumor landscapes.
Beyond direct receptor interactions, natriuretic peptides and their downstream pathways notably attenuate the tumor stromal matrix, reducing rigidity and facilitating drug delivery. Their capacity to modulate matrix proteins such as collagen I, fibronectin, and fibroblast activation protein (FAP) is crucial in overcoming barriers to therapeutic efficacy, especially in desmoplastic tumors like pancreatic ductal adenocarcinoma.
The therapeutic potential of harnessing natriuretic peptides transcends conventional modalities, introducing opportunities for multi-targeted approaches that could surmount resistance mechanisms inherent in monotherapies. Endogenous cardiac peptides have demonstrated remarkable anticancer activities across diverse cancers, eliminating substantial tumor burdens in preclinical models. By concurrently targeting proliferation, angiogenesis, immune suppression, and extracellular matrix remodeling, these peptides exemplify a promising template for next-generation anticancer agents.
Nevertheless, challenges remain in translating these insights into clinical realities. The dualistic and concentration-dependent effects of natriuretic peptides require meticulous titration and delivery strategies to harness their antitumor potential without inadvertently promoting oncogenesis. Pharmacokinetic limitations, receptor heterogeneity, and tumor-specific microenvironmental interactions add additional layers of complexity demanding integrated research approaches.
In conclusion, the natriuretic peptide receptor family ushers a paradigm shift in understanding tumor biology, elucidating a regulatory nexus that interlaces cardiovascular signaling, immune modulation, and oncogenic pathways. As research uncovers their multifaceted roles, these receptors stand poised to become linchpins for innovative cancer therapeutics, blending biochemical precision with the nuanced demands of tumor heterogeneity. Future clinical interventions leveraging natriuretic peptides and receptor modulators hold immense promise for enhancing treatment efficacy, overcoming resistance, and ultimately improving patient outcomes.
Subject of Research: The role and therapeutic potential of the natriuretic peptide receptor family (NPRA, NPRB, NPRC) in malignant tumors, focusing on their dual and context-dependent roles in tumor biology and tumor microenvironment modulation.
Article Title: The role and clinical value of natriuretic peptide receptor family in malignant tumor
Article References:
Quan, C., Shao, W., Yang, Y. et al. The role and clinical value of natriuretic peptide receptor family in malignant tumor. Cell Death Discov. 11, 412 (2025). https://doi.org/10.1038/s41420-025-02656-w
Image Credits: AI Generated
