Chronic inflammation is a hallmark of hepatocellular carcinoma (HCC) and is closely linked to aberrant arachidonic acid (AA) metabolism; however, whether AA mobilization is driven by defined upstream regulatory mechanisms and can be therapeutically targeted remains largely unresolved. Here, we identify cytosolic phospholipase A2 (cPLA2) as a central regulator of AA-dependent inflammatory signaling in hepatocarcinogenesis and a direct pharmacological target of nuciferine (NF). Using diethylnitrosamine (DEN)/carbon tetrachloride (CCl4)-induced HCC mouse models with transcriptomic and lipidomic profiling, we show that cPLA2 activation is progressively elevated during tumorigenesis, leading to excessive eicosanoid production that fuels NF-κB-driven inflammation. NF markedly suppresses tumor burden, fibrosis, and inflammatory signaling, accompanied by broad inhibition of AA metabolism. Mechanistically, NF directly binds to the C2 domain of cPLA2, disrupting Ca2 +-dependent membrane translocation and attenuating its activation. Importantly, Pla2g4a deficiency significantly attenuates hepatocarcinogenesis and abolishes the therapeutic effects of NF, establishing cPLA2 as essential for its antitumor activity. In human HCC, increased cPLA2 activation correlates with increased AA metabolism, inflammatory signatures, and poor patient survival. These findings uncover cPLA2-dependent AA metabolism as a critical inflammatory axis in HCC and identify NF as a direct cPLA2-targeting agent, highlighting a pharmacologically actionable metabolic node for liver cancer therapy.

Inefficient clearance of tumor-associated cellular debris sustains chronic inflammation and reinforces tumor-promoting immune niches in the colorectal cancer (CRC), yet strategies to selectively enhance macrophage-mediated cellular debris clearance remain largely unexplored. Here, we engineered a dual-targeted oral nanoplatform based on probiotic-derived extracellular vesicles (EVs) for selective delivery of astaxanthin (AXT-EVs) to tumor-associated macrophages (TAMs) in inflamed colonic tissues. Following oral administration, AXT-EVs preferentially accumulated within TAMs and induced functional reprogramming toward enhanced inflammatory debris resolution. Internalized AXT downregulates bridging integrin 2 (BIN2), a previously unrecognized negative regulator of macrophage phagocytic remodeling, thereby restoring macrophage-mediated clearance of tumor-associated cellular debris and disrupting debris-driven inflammatory amplification. In murine CRC models, AXT-EVs significantly inhibited tumor progression, alleviated intestinal inflammation and restored epithelial barrier integrity. Our findings identify defective macrophage debris clearance as a therapeutically targetable driver of colorectal tumorigenesis and establish a probiotic nanovesicle-based strategy as an immune-modulating platform for restoring tissue clearance homeostasis.

Cancer is sustained not only by pro-inflammatory signaling but also by inadequate restoration of tissue homeostasis, e.g., failed or dysregulated resolution. Specialized pro-resolving mediators (SPMs) are enzymatically generated lipid autacoids that actively coordinate termination of inflammation, including limiting neutrophil influx, stimulating macrophage efferocytosis, counter-regulating inflammatory mediator production, and supporting tissue repair and regeneration. In oncology, these processes intersect with tumor progression, perioperative biology, treatment-induced cell death, immunotherapy responsiveness, and late metastatic recurrence. Since 2021, major advances have reframed how we view SPMs in the context of cancer: (i) efferocytosis has emerged as a central but paradoxical mechanism that can both suppress debris-driven inflammation and enable tumor immune escape; (ii) resolution-phase macrophage mediators have been reported to target dormant disseminated tumor cells and their fibrotic niche; (iii) resolution defects linked to impaired SPM biosynthesis (including ALOX15 loss) may explain inconsistent omega-3 prevention trials; (iv) neutrophil extracellular traps (NETs) have become a rapidly expanding interface between inflammation, therapy stress, and metastatic risk; and (v) mechanistic updates, including SPM receptor signaling models, have sharpened the need for rigorous, context-aware interpretation. This chapter focuses specifically on cancer biology and translation, positioning SPMs as unique host-directed modulators with attractive potential for therapeutic intervention in cancer treatment and cancer prevention. Rather than blocking inflammation, SPMs actively reprogram inflammatory responses to maintain tumor dormancy and precancer conditions. This distinction is particularly relevant in cancer, where chronic non-resolving inflammation arises not only from tumor biology itself but also from therapeutic interventions such as surgery, chemotherapy, cytotoxic and immune-targeting therapy, and radiation.

INTRODUCTION: Inflammation is causally related to cancer progression and cardiovascular toxicities of anticancer treatments. Fine particulate matter (PM2.5) air filtration lowers interleukin-6 and C reactive protein (CRP) levels in high-risk cardiopulmonary groups, though potential synergistic or confounding effects with routine medications-statins, cyclo-oxygenase-2 inhibitors, beta-blockers-remain poorly understood. Whether overnight in-bedroom PM2.5 air filtration effectively reduces inflammation and prothrombotic biomarkers in survivors of adult-onset cancer at high cardiovascular toxicity risk is unknown.

METHODS AND ANALYSIS: BREATHS is a series of randomised, adaptive, blinded, placebo-controlled N-of-1 trials conducted in densely populated urban areas of Valencia, Spain, during winter when PM2.5 concentrations historically exceed WHO guidelines. Eligible participants are aged ≥18 years with a history of breast, colorectal, prostate, lung or haematological cancer, prior cardiotoxic cancer therapy and CRP ≥3 mg/L. Each participant will undergo up to three cycles, each comprising two 14-day periods of advanced submicron air filtration (clean air delivery rate: 275 m3/hour nightly) or placebo (sham filtration), in random order. Sequence duration ranges from 4 weeks to 12 weeks, depending on whether a clinically meaningful CRP reduction (<2 mg/L or ≥35% relative to placebo) is achieved during active treatment of each cycle. Non-responders will enter an open-label phase (OLP) of two 14-day periods: no treatment followed by continuous filtration. The primary endpoint is change in CRP between active and placebo phases. Secondary endpoints include changes in serum amyloid A, haemoglobin A1c and blood pressure. Indoor and outdoor particulate exposure will be quantified using paired real-time monitors at each home.

ETHICS AND DISSEMINATION: The trial protocol was approved by the research ethics committees of University College London (REC UCL: 22105/001), Doctor Peset University Hospital (CEIm: 044/25) and General University Hospital of Valencia (CEIm: 1/2026 EO-PS), Spain. Results will be presented at relevant conferences and published in peer-reviewed journals.

TRIAL REGISTRATION NUMBER: NCT06778122.

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Nascetur nisi, tortor velit et ipsum commodo. Tempor massa, non suscipit at sagittis morbi eget euismod.

Lacus, ultrices in ultrices tellus odio nunc urna. Massa aenean sed ipsum praesent enim. Porttitor iaculis augue pulvinar nam feugiat. Aliquam morbi ut ultricies elementum adipiscing purus proin semper. Viverra accumsan tempus, vitae auctor a. Dictumst cras dui sit feugiat. Enim nulla pulvinar urna sit eu placerat.

Nascetur nisi, tortor velit et ipsum commodo. Tempor massa, non suscipit at sagittis morbi eget euismod.

Lacus, ultrices in ultrices tellus odio nunc urna. Massa aenean sed ipsum praesent enim. Porttitor iaculis augue pulvinar nam feugiat. Aliquam morbi ut ultricies elementum adipiscing purus proin semper. Viverra accumsan tempus, vitae auctor a. Dictumst cras dui sit feugiat. Enim nulla pulvinar urna sit eu placerat.

Nascetur nisi, tortor velit et ipsum commodo. Tempor massa, non suscipit at sagittis morbi eget euismod.

Lacus, ultrices in ultrices tellus odio nunc urna. Massa aenean sed ipsum praesent enim. Porttitor iaculis augue pulvinar nam feugiat. Aliquam morbi ut ultricies elementum adipiscing purus proin semper. Viverra accumsan tempus, vitae auctor a. Dictumst cras dui sit feugiat. Enim nulla pulvinar urna sit eu placerat.

Nascetur nisi, tortor velit et ipsum commodo. Tempor massa, non suscipit at sagittis morbi eget euismod.

Lacus, ultrices in ultrices tellus odio nunc urna. Massa aenean sed ipsum praesent enim. Porttitor iaculis augue pulvinar nam feugiat. Aliquam morbi ut ultricies elementum adipiscing purus proin semper. Viverra accumsan tempus, vitae auctor a. Dictumst cras dui sit feugiat. Enim nulla pulvinar urna sit eu placerat.

Nascetur nisi, tortor velit et ipsum commodo. Tempor massa, non suscipit at sagittis morbi eget euismod.

Lacus, ultrices in ultrices tellus odio nunc urna. Massa aenean sed ipsum praesent enim. Porttitor iaculis augue pulvinar nam feugiat. Aliquam morbi ut ultricies elementum adipiscing purus proin semper. Viverra accumsan tempus, vitae auctor a. Dictumst cras dui sit feugiat. Enim nulla pulvinar urna sit eu placerat.

Nascetur nisi, tortor velit et ipsum commodo. Tempor massa, non suscipit at sagittis morbi eget euismod.