Chronic Inflammation and Cancer Therapy: Molecular Mechanisms and Clinical Advances in Resolution Pharmacology

Abstract

Chronic inflammation is a pivotal pathophysiological process driving carcinogenesis, tumor progression, metastasis, and therapeutic resistance. While the termination of inflammation was historically viewed as a passive dissipation event, recent research has established it as an active biochemical program governed by Specialized Pro-resolving Mediators (SPMs). Based on cutting-edge research from 2022 to 2025 and clinical data, this review provides an in-depth analysis of the failure of lipid class switching, receptor signal transduction networks, the role of resolution-phase macrophages (M-res), and the Sulciner Effect. Furthermore, it highlights Resolution Pharmacology as the emerging fourth pillar of cancer therapy, particularly through nanomedicine and synergistic strategies with immune checkpoint inhibitors.

INTRODUCTION THE PARADIGM SHIFT IN INFLAMMATION AND CANCER BIOLOGY

Wounds that do not heal and modern reinterpretation

Since the 19th-century German pathologist Rudolf Virchow termed cancer ‘wounds that do not heal’, the correlation between inflammation and cancer has been a central theme in modern oncology. Acute inflammation is an essential bio-defense mechanism for eliminating pathogens and repairing tissue; however, when it fails to resolve and persists, it transitions into chronic inflammation, acting as a potent promoter of carcinogenesis (Dosser et al., 2025). Historically, the concept of targeting resolution pathways for drug development has been established for over a decade. As early as 2012, Lee reviewed resolvins not merely as biological byproducts but as ‘fascinating drug candidates’ capable of modulating chronic inflammatory diseases without immunosuppression (Lee, 2012). This foundational perspective laid the groundwork for expanding their therapeutic application from general inflammatory disorders to complex pathologies like the tumor microenvironment (Lee, 2012). Recent molecular biological studies have clearly demonstrated that chronic inflammation induces genomic instability via reactive oxygen species (ROS) and reactive nitrogen species (RNS), causes epigenetic modifications, and creates a microenvironment conducive to malignant cell proliferation (Tripathi et al., 2025). In particular, the sustained activation of inflammatory transcription factors such as NF-κB and STAT3 suppresses apoptosis and induces angiogenesis, cultivating fertile soil for tumor growth.

From passive dissipation to active resolution

The medical community previously regarded the termination of inflammation as a passive process resulting from the dilution or dissipation of pro-inflammatory signals. However, breakthrough discoveries over the last decade, particularly between 2022 and 2025, have revealed that inflammation resolution is a highly active and biochemically sophisticated process driven by endogenous lipid molecules known as specialized pro-resolving mediators (SPMs) (Lavy et al., 2021).

Recent findings presented at the ASCO 2025 Annual Meeting reaffirmed that cancer-related inflammation is not merely a byproduct of tumor growth but a key driver determining disease progression, metastatic potential, and resistance to anticancer therapies (Dosser et al., 2025). Consequently, modern cancer therapeutic strategies are evolving beyond simple ‘Anti-inflammation’ (inhibition) to ‘Resolution Pharmacology’. It is crucial to distinguish that while traditional anti-inflammatories (e.g., COX-2 inhibitors) block pro-inflammatory signals, they carry the risk of being ‘resolution toxic’ by inadvertently suppressing the biosynthetic precursors of SPMs. In contrast, SPMs actively inhibit inflammation and simultaneously promote tissue regeneration, thereby restoring homeostasis. This aims to restore and activate the body’s intrinsic resolution mechanisms.

PRECISE BIOSYNTHESIS OF SPECIALIZED PRO-RESOLVING MEDIATORS (SPMS)

Enzymatic mechanisms of lipid class switching and its collapse in cancer

The inflammatory response is not a linear event with a simple beginning and end, but a dynamic process where dominant lipid mediators change over time. In the initiation phase of acute inflammation, cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) are activated, using arachidonic acid (AA) as a substrate to explosively produce potent pro-inflammatory mediators such as prostaglandins (PGE2, PGD2) and leukotrienes (LTB4). These are essential for vasodilation and neutrophil recruitment. However, as time progresses, the enzymatic activity pattern within the tissue must undergo a dramatic shift known as ‘lipid class switching’. In this process, PGE2 induces the expression of 15-lipoxygenase-1 (ALOX15), stopping the production of pro-inflammatory substances and switching to a mode that produces SPMs using omega-3 and omega-6 fatty acids as substrates (Fig. 1) (Lee et al., 2025b). Specifically, arachidonic acid converts to lipoxins, eicosapentaenoic acid (EPA) to E-series resolvins (RvE), and docosahexaenoic acid (DHA) to D-series resolvins (RvD), protectins, and maresins.

Fig. 1.

The temporal dynamics of lipid class switching and its impairment in the tumor microenvironment. This schematic illustrates the physiological transition from the inflammation initiation phase to the resolution phase. During the Initiation Phase, arachidonic acid (AA) is predominantly metabolized by enzymes such as COX-2 and 5-LOX to generate pro-inflammatory mediators, including prostaglandins (e.g., PGE2) and leukotrienes (e.g., LTB4) (indicated by the solid red line). Crucially, the accumulation of PGE2 induces the transcription of 15-LOX-1, acting as the trigger for the lipid class switch (indicated by the curved arrow). This enzymatic shift redirects the metabolism of polyunsaturated fatty acids—arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic Acid (DHA)—towards the biosynthesis of specialized pro-resolving mediators (SPMs) (solid blue line). These SPMs include lipoxins (LXs), E-series resolvins (RvE), D-series resolvins (RvD), protectins (PD), and maresins (MaR). In the context of cancer (shaded region), this switching mechanism is disrupted (failed switching), leading to the persistence of pro-inflammatory signals (dotted red line, chronic inflammation) and a consequent deficiency in SPMs (dotted blue line, resolution deficit), which fosters a tumor-promoting microenvironment.

However, recent analyses of various solid tumor tissues, including colorectal cancer (CRC) and pancreatic cancer, reveal that this switching mechanism is severely disrupted (Soundararajan et al., 2025). Cancer cells and surrounding stromal cells suppress or silence the expression of 15-LOX-1, a key enzyme for SPM production, via epigenetic modifications. Consequently, tumor tissues maintain high concentrations of AA-derived inflammatory prostaglandins while levels of resolving lipoxins or resolvins remain significantly low. This state of ‘resolution deficit’ provides a favorable microenvironment for cancer cells to evade immune surveillance and promote their own growth and angiogenesis through sustained inflammatory signals. Therefore, therapeutic strategies must go beyond simply inhibiting COX-2 with NSAIDs and focus on restoring 15-LOX-1 expression or exogenously administering SPMs to forcibly induce class switching.

Transcellular biosynthesis and the pharmacology of aspirin-triggered SPMs

While SPM biosynthesis can occur within a single cell, it occurs more efficiently in vivo through transcellular biosynthesis pathways involving cooperation between two or more cell types (Lee, 2012). For example, during vascular inflammation, neutrophils use 5-LOX to convert Arachidonic Acid into an unstable intermediate, LTA4, and release it. Adjacent platelets or endothelial cells then take up this LTA4 and use their 12-LOX enzymes to convert it into active lipoxin A4 (LXA4) or lipoxin B4 (LXB4). This cooperative mechanism acts as a sophisticated control device to inhibit thrombosis and prevent excessive leukocyte extravasation.

Furthermore, aspirin possesses a unique anticancer mechanism distinct from other non-steroidal anti-inflammatory drugs (NSAIDs). While typical NSAIDs simply block COX enzyme activity, aspirin acetylates the active site of COX-2, altering the enzyme’s structure. This modified COX-2 can no longer produce inflammatory prostaglandins but interestingly acquires the ability to generate precursors like 18R-HEPE or 15R-HETE from omega-3 fatty acids or arachidonic acid (Gilligan et al., 2019). These precursors are then converted by 5-LOX into ‘aspirin-triggered SPMs (AT-SPMs)’, such as AT-RvD1 and AT-LXA4. These AT-SPMs are epimers of their naturally occurring native forms. Crucially, the difference in the stereochemical orientation (chirality) of the hydroxyl group (-OH) at the carbon 17 (or 18) position in these R-epimers sterically hinders access by metabolic enzymes such as 15-PGDH. Consequently, AT-SPMs are resistant to rapid degradation and have a much longer half-life in the body than native forms, allowing them to exert more potent and sustained anti-inflammatory and anticancer effects. This provides the molecular biological basis for the efficacy of low-dose aspirin therapy in preventing colorectal cancer and suggests the potential of AT-SPMs themselves as novel anticancer candidates.

The counter-regulatory mechanism: Anti-resolution factors and metabolic inactivation

While the failure of lipid class switching explains the deficiency of SPMs, recent studies suggest that the active destruction of these mediators by ‘Anti-resolution Factors’ is a critical driver of chronic inflammation and cancer progression. The concept of anti-resolution factors refers to molecules that actively interfere with the resolution process, preventing the clearance of apoptotic cells (efferocytosis) and maintaining the inflammatory signal.

A key anti-resolution factor identified in the tumor microenvironment is high-mobility group box 1 (HMGB1). HMGB1, a nuclear protein released by necrotic or stressed cells, acts as a damage-associated molecular pattern (DAMP) that not only amplifies inflammation but specifically dismantles the resolution machinery through enzymatic induction.

Research by Kang et al. (2015) elucidated that HMGB1 suppresses resolvin D1 (RvD1)-induced phagocytosis by upregulating 15-hydroxyprostaglandin dehydrogenase (15-PGDH). 15-PGDH is a key catabolic enzyme that oxidizes the 17-hydroxyl group of RvD1 into 17-oxo-RvD1, rendering it biologically inactive (Kang et al., 2015). This metabolic inactivation prevents RvD1 from triggering the receptor-mediated signaling required for macrophage phagocytosis, thereby blocking the clearance of cancer cell debris. Indeed, silencing 15-PGDH or using an inhibitor (TD23) restored phagocytic activity, highlighting 15-PGDH as a crucial checkpoint in resolution failure. Furthermore, HMGB1 orchestrates a sophisticated epigenetic regulation to inactivate lipoxins. Kang et al. (2017) demonstrated that HMGB1 downregulates the expression of miR-522-3p, a microRNA that normally suppresses prostaglandin reductase 1 (PTGR1) (Kang et al., 2017). The loss of miR-522-3p leads to the overexpression of PTGR1, an enzyme that inactivates LXA4 by reducing its double bond structure. This ‘HMGB1–miR-522-3p–PTGR1’ axis effectively depletes active LXA4 levels in the tissue, further inhibiting macrophage efferocytosis and perpetuating the inflammatory loop.

Expanding the spectrum of anti-resolution factors, soluble epoxide hydrolase (sEH) acts as another critical checkpoint in lipid mediator inactivation. sEH rapidly hydrolyzes epoxyeicosatrienoic acids (EETs)—potent anti-inflammatory mediators produced by cytochrome P450 epoxygenases—into their biologically less active diols (DHETs) (Imig and Hammock, 2009). Under normal physiological conditions, EETs exert significant anti-inflammatory effects by inhibiting NF-κB activation and reducing cytokine production. However, the upregulation or activity of sEH facilitates the metabolic inactivation of these beneficial lipids, thereby dampening the intrinsic resolution capacity of the tissue. Crucially, the role of the sEH-EET axis in cancer presents a unique therapeutic paradox. While preserving EETs via sEH inhibition effectively resolves inflammation in cardiovascular models, the scenario in the tumor microenvironment is more complex. EETs are known to promote endothelial cell proliferation and angiogenesis. Imig and Hammock (2009) highlight that while sEH inhibitors have anti-inflammatory potential, they might inadvertently accelerate tumorigenesis by enhancing tumor vascularization, as evidenced by the upregulation of EET-producing enzymes (CYP2J2) in various human tumors.

Therefore, unlike 15-PGDH inhibition which purely restores resolution, targeting sEH in cancer requires a precision medicine approach: balancing the anti-inflammatory benefits of EETs against their potential to drive tumor angiogenesis. This establishes sEH not only as an anti-resolution factor but also as a pivotal switch regulating the balance between inflammation resolution and tumor progression.

RECEPTOR AND NUCLEAR RECEPTOR SIGNAL TRANSDUCTION NETWORKS: MOLECULAR SWITCHES OF RESOLUTION

G-protein coupled receptor (GPCR) networks: ALX, GPR32, ChemR23, LGR6

SPMs bind to G-protein coupled receptors (GPCRs) on the cell membrane to induce rapid cellular responses within seconds. These receptors are not simple ‘on/off’ switches but perform ‘biased agonism’, selectively activating downstream signaling pathways depending on the ligand.

The most representative receptor, ALX/FPR2, binds LXA4 and RvD1 (Maderna et al., 2010). Activation of this receptor inhibits rapid intracellular calcium spikes and modulates ERK/MAPK and PI3K/Akt pathways to halt neutrophil migration (Fig. 2). Crucially, the expression of these SPM receptors is not limited to immune cells; they are also present on cancer cells, where they directly modulate metastatic potential. Lee et al. (2013) demonstrated that RvD1 binds to ALX/FPR2 and GPR32 on A549 lung cancer cells, effectively blocking TGF-β1-induced epithelial-mesenchymal transition (EMT). In this study, RvD1 treatment restored E-cadherin expression while suppressing mesenchymal markers such as N-cadherin and Vimentin, thereby inhibiting cancer cell migration and invasion. This suggests that the activation of GPCR networks by SPMs can directly reprogram the malignant phenotype of cancer cells beyond the regulation of the immune microenvironment (Lee et al., 2013). Particularly in the hepatocellular carcinoma (HCC) microenvironment, ALX/FPR2 activation has been shown to inhibit the secretion of cartilage oligomeric matrix protein (COMP) by cancer-associated fibroblasts (CAFs), thereby blocking the acquisition of stemness by cancer cells (Sun et al., 2019).

Fig. 2.

The G-Protein Coupled Receptor (GPCR) and Nuclear Receptor signaling network of SPMs. This diagram delineates the key receptor-mediated signaling pathways by which SPMs exert their pro-resolving and anti-tumor effects. SPMs bind to specific GPCRs on the cell membrane, initiating distinct downstream cascades. ALX/FPR2 serves as a receptor for RvD1 and LXA4, inhibiting ERK activation to halt neutrophil migration (Stop Signal) and engaging in biased agonism. The human-specific receptor GPR32 binds RvD1 with high affinity, triggering a phenotypic switch in macrophages towards a pro-resolving M-res state, characterized by enhanced phagocytosis. ChemR23 binds RvE1 and blocks the nuclear translocation of the inflammatory transcription factor NF-kB (NF-kB Nuclear Import Blocked), thereby suppressing the transcription of pro-inflammatory cytokines. LGR6 acts as a receptor for MaR1, mediating tissue regeneration signals. Furthermore, SPMs such as RvD1 can bypass membrane receptors or be internalized to interact with nuclear receptors like PPAR-gamma. Activated PPAR-gamma physically binds to nuclear NF-kB, preventing it from binding to DNA promoter regions (Inflammatory Gene Transrepression) and actively promoting its export from the nucleus back to the cytoplasm (Nuclear Export). This comprehensive mechanism highlights how SPMs reprogram the cellular response from inflammation to resolution.

The human-specific receptor DRV1 (GPR32) has a high affinity for RvD1. Binding of RvD1 to GPR32 induces beta-arrestin recruitment and cAMP release within macrophages, altering their morphology and explosively increasing phagocytosis (Shan et al., 2020). Research has shown that GPR32-deficient macrophages fail to exhibit antitumor effects even when treated with RvD1, proving this receptor is a key gateway for human immune resolution.

DRV2 (GPR18) is another critical receptor, particularly implicated in controlling cancer metastasis. It serves as a high-affinity receptor for RvD2. Activation of DRV2 on vascular endothelial cells strengthens adherens junctions, reinforcing the endothelial barrier and preventing tumor cell extravasation into distant tissues. Simultaneously, DRV2 activation on macrophages enhances their non-phlogistic clearance capabilities, providing a dual protective mechanism against metastasis.

The ChemR23 (ERV1) receptor binds RvE1 and blocks the nuclear translocation of the inflammatory signal NF-κB, suppressing the transcription of inflammatory cytokines like IL-6 and TNF-alpha. In oral cancer and bone metastasis models, ChemR23 activation inhibited osteoclast differentiation and promoted osteoblast activity, demonstrating a protective effect on bone tissue (AlZahrani et al., 2024).

Finally, the LGR6 receptor binds MaR1 to mediate tissue regeneration signals. Activated LGR6 crosstalks with the Wnt/beta-catenin pathway via leucine-rich repeats, regulating epithelial cell proliferation and migration (Chiang et al., 2023). Studies showing that LGR6 gene mutations lead to reduced defense against viral infections and a higher probability of transitioning to chronic inflammation suggest this receptor is essential for maintaining tissue homeostasis (Gomez et al., 2024). Additionally, MaR1 is known to exert potent analgesic effects by modulating the TRPV1 channel, further improving patient quality of life in the context of cancer pain.

Nuclear receptors and genomic reprogramming via transcriptional regulation

Cutting-edge research reveals that SPMs can bypass membrane receptors or enter cells to directly regulate Nuclear Receptors, fundamentally altering gene expression programs. This implies that SPM effects are not limited to transient signaling but have long-term consequences determining cell fate.

PPAR-gamma (Peroxisome Proliferator-Activated Receptor gamma) is a major target of SPMs, particularly resolvins and protectins. RvD1 or its metabolites induce PPAR-gamma activation in the cytoplasm. Activated PPAR-gamma translocates to the nucleus and physically interacts with NF-κB and AP-1, the master switches of inflammation, preventing them from binding to DNA promoter regions via a mechanism known as ‘Transrepression’ (Fig. 2) (Sulciner et al., 2018). Furthermore, this interaction actively promotes the nuclear export of the NF-kB complex back into the cytoplasm, effectively terminating the inflammatory transcriptional program. This fundamentally blocks the gene expression of inflammatory cytokines, chemokines, and MMPs (Matrix Metalloproteinases) that facilitate cancer cell invasion.

Additionally, SPMs inhibit the phosphorylation of STAT3. In colorectal cancer cells, IL-6 activates STAT3 to induce Epithelial-Mesenchymal Transition (EMT) and support cancer cell survival; RvD1 blocks this pathway, restoring E-cadherin (epithelial marker) expression and lowering Vimentin (mesenchymal marker) expression (Du et al., 2024). In lung cancer models, Aspirin-Triggered Resolvin D1 (AT-RvD1) was shown to inhibit the mTOR pathway, regulating cancer cell metabolism and reducing ROS generation that causes oxidative stress (Liu et al., 2016). This demonstrates that resolution agonists can reverse cancer cell energy metabolism (Glycolysis) to oxidative phosphorylation similar to normal cells (Metabolic Reprogramming), cutting off the proliferation power of cancer cells. Furthermore, SPMs exert control over transcriptional networks to prevent the acquisition of stem-like traits in cancer cells. Notably, RvD1 has been shown to suppress the expression of ZEB1 (Zinc Finger E-Box Binding Homeobox 1), a master transcription factor of EMT (Lee et al., 2013). By inhibiting ZEB1, RvD1 disrupts the transcriptional program that drives the transition from an epithelial to a mesenchymal phenotype. This finding highlights the capacity of SPMs to terminate the initiation signals of EMT provided by the chronic inflammatory microenvironment at the genomic level (Lee, 2018; Lee et al., 2013).

REPROGRAMMING THE TUMOR MICROENVIRONMENT: M-RES MACROPHAGES AND THE SULCINER EFFECT

Phenotypes and functional superiority of M-res macrophages

Tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) play a dual role in either aiding or inhibiting cancer progression. Traditionally classified into inflammatory M1 and tumor-promoting M2, this dichotomy is overly simplistic from the perspective of resolution pharmacology. Macrophages induced by SPMs exhibit a third, ideal anticancer phenotype known as resolution-phase macrophages (M-res) (Liu et al., 2023).

While M-res macrophages may share some surface markers (e.g., CD206) with M2 macrophages, they are functionally distinct. M2 macrophages secrete vascular endothelial growth factor (VEGF) or TGF-beta to aid cancer growth and metastasis and suppress immunity. In contrast, M-res macrophages potently inhibit the secretion of these tumor-promoting factors (Lavy et al., 2021). Simultaneously, unlike M1 macrophages, M-res do not release excessive pro-inflammatory cytokines (IL-1beta, TNF-alpha) that damage tissue.

The core function of M-res is the maximization of phagocytosis/efferocytosis. M-res macrophages possess an unparalleled ability to recognize and devour dead cancer cells, neutrophils, and cell debris. They neutralize ‘Don’t eat me’ signals like CD47 and rapidly clear cell debris, fundamentally eliminating the source of inflammation within the TME. Furthermore, M-res maintain or enhance antigen presentation capabilities to activate lymphocytes, serving as a bridge to help the adaptive immune system better attack cancer cells.

The Sulciner Effect: Preventing recurrence through debris clearance

Chemotherapy and radiotherapy are effective in inducing massive cancer cell death but inevitably leave behind vast amounts of apoptotic cells and cell debris. If this debris is not removed rapidly, cell membranes rupture, releasing toxic intracellular contents and DAMPs (Danger-Associated Molecular Patterns) that stimulate surrounding living cancer cells and trigger a pro-tumorigenic cytokine storm. Essentially, dead cancer cells become fertilizer for the living ones.

Groundbreaking studies from 2023-2024 have proven that SPMs like Resolvins (RvD1, RvD2) play a decisive role in breaking this vicious cycle, a phenomenon termed ‘The Sulciner Effect’ (Sulciner et al., 2018). The Sulciner Effect refers to the mechanism where SPMs stimulate macrophages to rapidly and cleanly clear the cell debris generated by therapy. In animal models, administration of chemotherapy agents (Cisplatin, Gemcitabine) alone resulted in inflammation due to debris accumulation and subsequent tumor regrowth. However, when combined with resolvins, macrophage phagocytosis was enhanced, debris was cleared, and consequently, tumor growth and metastasis were dramatically suppressed (FIg. 3).

Fig. 3.

Reprogramming of tumor-associated macrophages into a resolution phenotype (M-res) and the Sulciner Effect. (A) Phenotypes: This panel compares three distinct macrophage polarization states within the tumor microenvironment. M1 (Pro-inflammatory) macrophages release cytotoxic cytokines such as IL-6 and TNF-alpha, exacerbating tissue damage. M2 (Tumor-Promoting) macrophages secrete angiogenic factors like VEGF, facilitating tumor growth and repair. In contrast, M-res (Resolution-phase) macrophages, induced by SPMs, exhibit a unique phenotype characterized by the enhanced clearance of cellular debris without promoting inflammation or tumor growth. (B) The Sulciner Effect: This panel illustrates the critical role of M-res macrophages in the post-therapeutic clearance of cancer cell debris. Without SPMs (left), the accumulation of necrotic debris triggers secondary inflammation and increases the risk of recurrence. With SPM treatment (right), M-res macrophages actively phagocytose debris (The Sulciner Effect), effectively preventing secondary inflammation and recurrence, thereby restoring tissue homeostasis.

This suggests that SPMs are not merely anti-inflammatory agents but essential partners that complement the inherent limitations of cytotoxic therapy (debris accumulation and secondary inflammation). Therefore, future anticancer protocols must include both axes: Cytotoxicity (killing cancer cells) and Clearance (removing debris).

Modulation of stromal senescence and autophagy

Beyond immune cells, the tumor microenvironment (TME) is composed of stromal cells, such as fibroblasts, whose senescence contributes to cancer progression via the senescence-associated secretory phenotype (SASP) (Lee et al., 2025a). Recent evidence suggests that SPMs can rejuvenate these stromal components.

Kim et al. (2021) revealed that RvD1 protects dermal fibroblasts from oxidative stress-induced senescence by inducing autophagy. Mechanistically, RvD1 regulates the miR-1299/ARG2/ARL1 axis, thereby promoting autophagic flux and maintaining cellular homeostasis (Kim et al., 2021). Furthermore, LXA4 has been shown to antagonize TGF-β1 signaling, effectively inhibiting the differentiation of fibroblasts into pro-tumorigenic cancer-associated fibroblasts (CAFs) and preventing fibrosis-associated matrix stiffening (Chandrasekharan and Sharma-Walia, 2015).

Crucially, the protective role of SPMs extends to the regulation of the NLRP3 inflammasome. By inhibiting NLRP3 activation, SPMs not only mitigate oxidative stress but also directly dampen the secretion of key SASP factors like IL-6 and IL-8, thereby blocking the inflammatory feedback loop that drives tumor invasiveness (Lopategi et al., 2019). This implies that SPMs can prevent the formation of an inflammatory, pro-tumorigenic stroma by controlling senescence and activating autophagy in fibroblasts, offering a multi-faceted approach to reprogramming the TME.

CANCER-SPECIFIC CLINICAL RESEARCH DATA AND STATISTICAL SIGNIFICANCE (2022-2025)

Breast & gynecologic cancers: Genotype-tailored therapy and biomarkers

In breast cancer, the impact of a patient’s genetic background on lipid metabolism and resolution capacity was clarified in a 2024 study. In breast cancer patients carrying BRCA1/2 mutations, administration of omega-3 (DHA) supplements resulted in a statistically significant surge in plasma RvD1 and RvD2 concentrations compared to the non-mutated control group (Molfino et al., 2025). Conversely, high-risk women with a family history but no mutations showed poor SPM production despite DHA supplementation. This suggests that BRCA genes are involved in regulating lipid-oxidizing enzymes as well as DNA repair, providing strong evidence that SPM-based preventive and adjuvant therapies could be highly effective for BRCA mutation carriers. Additionally, lower plasma RvD1 levels were associated with poor-prognosis subtypes like triple-negative breast cancer (TNBC) and high Ki-67 proliferation indices, indicating RvD1’s potential as a prognostic factor (Molfino et al., 2024).

In a cohort study of 198 cervical cancer patients, the group with high plasma EPA levels showed significantly higher progression-free survival (PFS) after concurrent chemoradiotherapy (CCRT) compared to the low EPA group. Multivariate analysis confirmed high EPA levels as an independent predictor of improved PFS (Hazard Ratio [HR]: 0.263; 95% CI: 0.088-0.784; p=0.016) (Ping et al., 2024).

Gastrointestinal cancers (pancreatic, gastric, colorectal): Diagnostic and therapeutic innovation

Pancreatic ductal adenocarcinoma (PDAC) is difficult to detect early and has an extremely poor prognosis. In a recent case-control study, serum RvD1 levels in pancreatic cancer patients (mean 728.57 pg/mL) were approximately 40% lower than in healthy controls (mean 1169.24 pg/mL) (p<0.001). Notably, this level significantly differentiated pancreatic cancer patients from those with chronic pancreatitis, suggesting its potential as a new diagnostic biomarker to complement or replace CA19-9 (Pekmezci et al., 2025).

In gastric cancer therapy, immunotherapies restoring macrophage function are gaining attention. Cancer cells express CD47 (Don’t eat me signal) to evade macrophages. Phase 2 clinical results for Evorpacept, a CD47 blocker, were presented at ASCO GI 2025. In HER2-positive gastric cancer patients, adding Evorpacept to Trastuzumab + Chemotherapy resulted in an objective response rate (ORR) of 48.9%, significantly outperforming the control group (~33%). Even more encouraging, the median duration of response (mDOR) was 15.7 months, extending more than 6 months beyond the control group’s 9.1 months. This proves that releasing the brake on macrophage phagocytosis translates into survival benefits for patients (Shitara et al., 2025).

The CHALLENGE study, a large-scale randomized trial in colorectal cancer patients, demonstrated the power of lifestyle intervention. High-intensity physical activity in patients who completed adjuvant therapy resulted in a disease-free survival (DFS) hazard ratio (HR) of 0.72 (p=0.017), indicating that exercise alone could reduce recurrence risk by 28%. This is attributed to myokines secreted by muscles resolving systemic inflammation and promoting SPM production (Courneya et al., 2025).

THERAPEUTIC INTERVENTION STRATEGIES: NANOMEDICINE AND ICI SYNERGY

Innovation in SPM delivery via nanomedicine

The major technical barrier in resolution therapy has been the instability of lipid SPMs in the body, where they are rapidly oxidized or metabolized. To overcome this, researchers in 2024 developed nano-carriers using biodegradable polymers like polylactic acid (PLA) or liposomes (Fig. 4).

Fig. 4.

Biochemical Instability of SPMs and the Protective Mechanism of Nanocarriers. (A) Metabolic Attack by 15-PGDH: Naturally occurring specialized pro-resolving mediators (SPMs) such as Resolvin D1 (RvD1) and Maresin 1 (MaR1) are rapidly inactivated by 15-hydroxyprostaglandin dehydrogenase (15-PGDH). This catabolic enzyme oxidizes the essential hydroxyl groups, converting potent resolving lipids into inactive oxo-metabolites. (B) Nanoparticle-Mediated Protection: To prevent this metabolic degradation, SPMs are encapsulated within a polymeric core shielded by a lipid bilayer shell. This nanostructure provides a physical barrier that prevents 15-PGDH from accessing the cargo, thereby enhancing the half-life and therapeutic efficacy of the delivered SPMs.

A notable achievement is the development of thermostable PLA nanoparticles encapsulating MaR2 (Miranda et al., 2023). These nanoparticles have excellent stability at room temperature, eliminating the need for cold chains, and can safely deliver MaR2 to inflamed intestinal mucosa sites without degradation by gastric acid upon oral administration. In colitis mouse models, administration of these nanoparticles significantly promoted epithelial cell migration and proliferation compared to controls (p<0.05) and restored inflammatory cytokine levels to normal. This suggests a potential role as a preventive vaccine preventing the progression of inflammatory bowel disease (IBD) to colorectal cancer. Additionally, research is underway to design SPM nanoparticles that selectively accumulate in tumor tissues utilizing the EPR effect (enhanced permeability and retention effect) due to the high vascular permeability of tumors (Li et al., 2024).

Synergy with Immune Checkpoint Inhibitors (ICI): Turning ‘cold’ tumors ‘hot’

Current mainstream cancer therapies like Pembrolizumab (Keytruda) work by releasing the brakes on T cells, but they are limited by cold tumors where immune cells cannot penetrate the tissue, or by immune-related adverse events (irAEs) due to excessive immune activation. Moreover, the potential of SPMs extends to managing systemic inflammation associated with cancer therapy. Severe inflammatory responses, such as the cytokine storm seen in viral infections, share mechanistic parallels with the cytokine release syndrome (CRS) observed in cancer immunotherapy. Lee (2021) highlighted that SPMs can effectively mitigate the SARS-CoV-2 induced cytokine storm by regulating pro-inflammatory mediators. This suggests a promising translational avenue where SPMs could be utilized as adjuvants to dampen systemic toxicity and CRS in cancer patients undergoing aggressive immunotherapies, thereby broadening the therapeutic window (Lee, 2021).

SPMs are perfect partners to complement these ICI limitations. First, SPMs normalize abnormal tumor vasculature and lower interstitial pressure, opening pathways for T cells to penetrate deep into tumor tissues (Wetzel et al., 2022). This converts cold tumors into hot tumors teeming with immune cells, increasing ICI response rates. Second, SPMs do not inhibit the anticancer activity (cytotoxicity) of T cells but selectively suppress only unnecessary inflammatory responses like excessive neutrophil activity or cytokine storms. This allows for the management of common ICI side effects such as colitis, pneumonitis, and dermatitis without steroids, helping patients continue treatment without interruption. Melanoma patient data showing an improved recurrence-free survival (RFS) hazard ratio of 0.64 when combining Pembrolizumab with anti-inflammatory strategies supports the clinical validity of this combination (Wetzel et al., 2022) (Fig. 5).

Fig. 5.

Therapeutic strategies utilizing Specialized Pro-resolving Mediators (SPMs): Nanomedicine and synergistic combination with Immune Checkpoint Inhibitors (ICIs). (Left) Nanomedicine: This panel depicts an advanced drug delivery system designed to overcome the rapid metabolic inactivation of SPMs. Maresin 2 (MaR2) is encapsulated within a thermostable Polylactic Acid (PLA) nanoparticle with a core-shell structure. This formulation protects the bioactive lipid from degradation by gastric acid, enabling oral delivery and targeted release at the inflamed intestinal mucosa to resolve inflammation and promote tissue repair. (Right) Synergy with ICI: This panel illustrates the synergistic effect of combining SPM treatment with Immune Checkpoint Inhibitors (ICIs). In a cold tumor (top), tangled and abnormal vasculature restricts the infiltration of cytotoxic T cells. SPM treatment (bottom) normalizes tumor blood vessels and reduces interstitial pressure, transforming the microenvironment into a hot tumor. This facilitates the infiltration of T cells, thereby enhancing the efficacy of ICIs while potentially mitigating immune-related adverse events.

Lifestyle intervention and precision nutrition

ASCO 2025 emphasized strategies to maximize endogenous SPM production through lifestyle modification alongside pharmacotherapy. In a Randomized Controlled Trial (RCT) involving Non-Small Cell Lung Cancer (NSCLC) patients, high-dose Omega-3 fatty acid supplementation (2.4g daily) during postoperative chemotherapy resulted in less weight loss (nutritional preservation) and significant reductions in systemic inflammatory markers like CRP, IL-6, and

TNF-alpha compared to the control group (Gui et al., 2023). Furthermore, analysis of the UK Biobank cohort of 500,000 individuals revealed that the top 20% group with high plasma Omega-6/Omega-3 ratios had a 14% higher cancer mortality rate compared to the bottom 20%, along with increased cardiovascular mortality (Zhang et al., 2024). This epidemiologically proves that reducing Omega-6 (pro-inflammatory precursor) and increasing Omega-3 (resolution precursor) intake in modern diets is essential for cancer prevention and improving prognosis.

CONCLUSION

Research outcomes from 2022 to 2025 provide a clear direction that cancer therapy must evolve beyond simple inhibition of inflammation to active resolution. Chronic inflammation is fundamentally a failure of resolution mechanisms, and SPMs are the biological keys to breaking this vicious cycle and clearing cancer cell debris to prevent recurrence. Future research must focus on the clinical translation of nanomedicine technologies for stable delivery of unstable lipid mediators and the validation of lipidomics-based precision biomarkers, emphasizing the necessity of standardized, rigorous LC-MS/MS-based targeted lipidomics over traditional immunoassays for clinical application. Resolution Pharmacology will establish itself as the fourth pillar of cancer therapy, integrated with surgery, chemotherapy, radiotherapy, and immunotherapy to maximize therapeutic efficacy and minimize side effects.