Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear transcription factor that governs helper T cell (Th) immunometabolism and functional differentiation by regulating gene transcription, cellular metabolism, and cytokine microenvironment. In Th1 cells, PPARγ primarily regulates interferon-γ (IFN-γ) secretion. Within Th2 cells, it influences GATA-binding protein 3 (GATA3) expression and provides metabolic support for normal cellular functions. In Th17 cells, it inhibits RAR-related orphan receptor γt (RORγt) transcription and suppresses inflammatory signals, thereby alleviating Th17-mediated inflammatory responses. In Tregs, PPARγ aids in cell differentiation by activating forkhead box P3 (Foxp3) transcription and inducing metabolic reprogramming. In Th9 cells, PPARγ promotes the secretion of IL-9. Within Tfh cells, the deficiency of PPARγ leads to an increase in B cell leukemia/lymphoma 6 (Bcl-6) expression. Notably, PPARγ agonists and antagonists effectively preserve Th-cell homeostasis by targeting PPARγ-mediated metabolic and signaling pathways. This review summarizes PPARγ as a crucial transcription factor governing Th-cell responses and elucidates its underlying molecular mechanisms. Based on the evidence predominantly derived from animal models, it lays a foundation for translational research of PPARγ-targeted immunotherapy.
Photothermal therapy (PTT) is a local treatment that uses photothermal conversion agents (PTAs) to absorb light and produce heat in tumor tissue. The direct result is tumor ablation. At the same time, heat-damaged tumor cells may undergo immunogenic cell death (ICD). This process is often accompanied by the release of damage-associated molecular patterns (DAMPs), followed by dendritic cell activation and antigen presentation. Because of this immune effect, PTT has been explored as a partner for immunotherapy. It may be useful in tumors where antigen presentation is weak or where the immune microenvironment is highly suppressive. However, local heating alone usually cannot produce a long-lasting systemic immune response. Its effect on distant metastasis is also limited. For this reason, PTT is now often combined with immune checkpoint blockade, adoptive cell therapy, cancer vaccines, and other immune-based strategies. This review discusses the link between PTT-induced tumor damage and antitumor immune activation. It classifies and compares the structural optimization ideas, optical properties, biological safety, and application limitations of organic and inorganic photothermal materials. It summarizes the six mainstream combination schemes of photothermal therapy with immune checkpoint inhibitors, adoptive cell therapy, tumor vaccines, cytokine therapy, oncolytic virus therapy, and bispecific antibody therapy. It analyzes the synergistic anti-tumor mechanisms and the latest preclinical research progress of various combination strategies. Finally, it sorts out the core bottlenecks that restrict the clinical transformation of photothermal immunotherapy and proposes corresponding optimization development prospects.
Lysine crotonylation(Kcr), an important protein post-translational modification, establishes a connection between cellular metabolism and epigenetic regulation. This modification utilizes crotonyl-CoA as a donor and is co-regulated by “writers”, “erasers” and “readers”. Furthermore, it participates in key biological processes including gene transcription, metabolic reprogramming, DNA damage repair, and remodeling of the tumor immune microenvironment. Recent studies have demonstrated that crotonylation is dysregulated in various malignant tumors, including breast cancer, colorectal cancer, liver cancer, lung cancer, and glioma. It drives tumor proliferation, invasion, metastasis, and drug resistance by influencing metabolic enzyme activity, chromatin status, DNA repair efficiency, and immune signaling pathways. Lysine crotonylation demonstrates significant environmental-dependence across different cancers; Not only can it promote the malignant phenotype of tumor cells, but it can also potentiate the response to immunotherapy under specific metabolic conditions. Preclinical studies have explored therapeutic strategies targeting tumor crotonylation, including metabolic interventions, enzymatic regulation, and combination immunotherapy; however, these approaches remain investigational and have not been clinically validated. This narrative review summarizes the molecular mechanisms, biological functions, and current advances of crotonylation in diverse malignancies, and highlights unresolved questions and emerging therapeutic hypotheses.
Interferons (IFNs) are cytokines that play crucial roles in antiviral activity, anti-proliferation, stimulation of cytotoxic T cells, and modulation of host immune responses. Like other cytokines, IFNs bind their receptors on the cell surface to activate intracellular signal transduction. The major signaling pathway activated by IFNs is the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, which leads to the transcriptional activation of interferon-stimulated genes (ISGs). More than 300 ISGs can be upregulated by IFNs. Among these ISGs are a myriad of antiviral effectors, including ISG15, myxovirus resistance 1 (MX1), ribonuclease L (RNase L), and protein kinase R (PKR). Given the potent antiviral responses elicited by IFN-activated JAK/STAT signaling, viruses have evolved diverse strategies to antagonize this pathway during infection. In this review, recent progress in understanding the functions of ISGs is summarized, with particular emphasis on viral antagonism of ISG-mediated antiviral responses.
Osteoarthritis (OA) is increasingly recognized as a whole-joint disease shaped by chronic low-grade inflammation, matrix damage, mechanical stress, and failed tissue repair. Beyond the traditional view of cartilage wear, emerging evidence indicates that immune–chondrocyte ligand–receptor (LR) communication plays a central role in translating microenvironmental cues into disease-relevant chondrocyte phenotypes. In this narrative review, we summarize major immune-derived or inflammation-amplified LR axes that regulate OA progression, including cytokine pathways such as IL-1β–IL-1R, TNF-α–TNFR, IL-6–IL-6R/gp130, and IL-17–IL-17R; chemokine axes such as CXCL12–CXCR4 and CCL2–CCR2; DAMP–PRR pathways involving HMGB1, S100A8/A9, TLRs, and RAGE; and ECM-associated signaling through CD44 and integrins. These axes collectively drive chondrocyte catabolic activation, hypertrophic differentiation, senescence, inflammatory cell death, autophagy dysfunction, and impaired matrix repair. We further discuss how single-cell sequencing, spatial transcriptomics, multiplex imaging, and computational LR inference are redefining OA as a spatially organized disorder of immune–chondrocyte and multicellular joint communication. Finally, we highlight therapeutic opportunities, including receptor-level modulation, macrophage reprogramming, local intra-articular delivery, and LR-axis-based patient stratification. Understanding immune–chondrocyte LR networks may enable precision strategies that suppress pathological inflammation while preserving repair-oriented signaling in OA.
