Macrophages play diverse roles in development, homeostasis, and immunity. Accordingly, the dysfunction of macrophages is involved in the occurrence and progression of various diseases, such as coronavirus disease 2019 and atherosclerosis. The protective or pathogenic effect that macrophages exert in different conditions largely depends on their functional plasticity, which is regulated via signal transduction such as Janus kinase–signal transducer and activator of transcription, Wnt and Notch pathways, stimulated by environmental cues. Over the past few decades, the molecular mechanisms of signaling pathways in macrophages have been gradually elucidated, providing more alternative therapeutic targets for diseases treatment. Here, we provide an overview of the basic physiology of macrophages and expound the regulatory pathways within them. We also address the crucial role macrophages play in the pathogenesis of diseases, including autoimmune, neurodegenerative, metabolic, infectious diseases, and cancer, with a focus on advances in macrophage‐targeted strategies exploring modulation of components and regulators of signaling pathways. Last, we discuss the challenges and possible solutions of macrophage‐targeted therapy in clinical applications. We hope that this comprehensive review will provide directions for further research on therapeutic strategies targeting macrophage signaling pathways, which are promising to improve the efficacy of disease treatment.

IMA-1 targets the ALOX12-ACC1 interaction to both prevent and treat NASH without inducing hyperlipidemia.

ALOX12 drives NASH by inhibiting ACC1 lysosomal degradation across multiple species.

The antitumor activity demonstrated by DNA damage response inhibitors (DDRis) can be partially attributed to their capacity to enhance immune responses. However, the toxicity of DDRis to lymphocytes, particularly when a DDRi is combined with other treatments targeting cell cycle checkpoint kinases, indicates a need for the development of different DDRi treatment schedules. Here, we systematically assessed changes to the tumor immune microenvironment (TIME) in response to DDRis across various treatment timelines in ovarian cancer. Using single-cell analysis, we found that the sequential treatment with an inhibitor of poly(ADP-ribose) polymerase (PARPi), followed by an inhibitor of the cell cycle checkpoint kinase WEE1 (WEE1i), resulted in more effective cancer eradication and stronger antitumor immune responses in vivo, compared with mono- and concurrent therapy. Both sequential and concurrent treatment schedules could induce lethal DNA damage and activate the cGAS-STING pathway in cancer cells, but T cell viability was greater under sequential treatment. Proteomic analysis showed that T cells more quickly recovered from DNA damage after DDRi treatment compared with cancer cells. Both immune checkpoint therapy and CAR T cells were more effective when combined with sequential treatment compared with monotherapy treatment in a syngeneic high-grade serous ovarian cancer mouse model and in a treatment-resistant ovarian cancer patient-derived xenograft model. Our study demonstrated that sequential treatment with PARPi and WEE1i spared T cells from severe DNA damage and activated the cGAS-STING pathway in cancer cells, suggesting that antitumor immunity and control of tumor growth can be optimized through changes in treatment schedules.

Cancer-associated fibroblasts (CAFs) are central architects of immunosuppression and therapy resistance across malignancies, yet how tumor-intrinsic genomic instability instructs stromal reprogramming remains unresolved. Integrated single-cell transcriptomics and epigenomics of samples from patients with high-grade serous ovarian carcinoma revealed POSTN ⁺ myofibroblast-like cancer-associated fibroblasts (myCAFs) and effector regulatory T cells (eT _reg cells) as critical mediators of immunosuppression in tumors with high genomic instability. Mechanistically, unstable genomes activated tumor-intrinsic STING signaling, triggering WNT3a/7a secretion. WNT/β-catenin signaling in fibroblasts established a POSTN-dependent positive feedback loop that epigenetically locked cells into a POSTN ⁺ myCAF lineage. These myCAFs reciprocally expanded eT _reg cells and exhausted CD8 ⁺ T cells, thereby converting genomic instability–driven immune activation into suppression and limiting poly(ADP-ribose) polymerase inhibitor (PARPi) efficacy. Therapeutic POSTN blockade reinvigorated T cell cytotoxicity, depleted eT _reg cells, and potentiated PARP inhibition in ovarian and breast cancer models, overcoming resistance. Our work resolves the dual roles of genomic instability and identifies POSTN as a stromal-specific checkpoint to mediate immunosuppression in genomically unstable tumors.

Besides targeting tumor cells via canonical synthetic lethality, poly(ADP-ribose) polymerase inhibitors (PARPis) can remodel tumor immune microenvironment (TIME), which then affects PARPis’ anti-tumor capabilities. However, exact function of PARPis on TIME remains insufficiently explored. Here, by leveraging paired samples during neoadjuvant PARPi Niraparib treatment derived from a prospective clinical trial, we discovered that the expression of immune checkpoint ligand B7-H3 was induced by PARPis in cancer-associated fibroblasts (CAFs) of ovarian cancer. Depletion of B7-H3 in CAFs by using host cd276 (coding B7-H3) knockout mice or B7-H3 deficient fibroblast cells both boosted T cell functions and enhanced the anti-tumor capacities of PARPis in immunocompetent mouse models. Besides, increased B7-H3 on CAFs also attenuated the anti-tumor potentials of T cells in co-culture system. Mechanistically, PARPis blocked autophagic flux by inhibiting PIP4K2A expression, a critical regulator of autophagosome and lysosome fusion, and therefore dampening the lysosomal degradation of B7-H3. Importantly, neutralizing B7-H3 antibodies had synergistic effects with PARPis and achieved superior therapeutic efficacy than PARPis plus PD-1 blockade in a syngeneic mouse ovarian cancer model. Collectively, this study revealed an autophagy-mediated pathway by which PARPis contribute to immune evasion via enhanced B7-H3 accumulation on CAFs, highlighting the complexity of the regulation of PARPis on TIME and the potential application of combining PARPis with B7-H3 blockade in the treatment of ovarian cancer.