Bone and soft tissue sarcomas represent a heterogeneous group of malignancies arising from mesodermal tissues, presenting a formidable challenge in clinical management due to their rarity and histological diversity(Ducimetiere et al., 2011; Zachary Burningham, 2012; Zago Baltazar et al., 2024). Despite significant advancements in diagnostic techniques and therapeutic modalities, including surgery, chemotherapy, and radiotherapy, the prognosis for many sarcoma patients remains dismal, underscoring the pressing need for innovative therapeutic strategies(Fenzl, Mehrmann, Kremp, & Schneider, 2017; Krieg et al., 2011; Lochner, Menge, Vassos, Hohenberger, & Kasper, 2020).
Recently, there has been a growing appreciation for the role of programmed cell death (PCD) pathways in cancer biology(Bedoui, Herold, & Strasser, 2020; Hsu et al., 2021). Among these pathways, PANoptosis has emerged as a unique form of inflammatory PCD, marked by the activation of the PANoptosome complex, leading to pyroptosis, apoptosis, and necroptosis(Pandian & Kanneganti, 2022; Wang & Kanneganti, 2021). The dysregulation of PANoptosis has been linked to various human diseases, including cancer, underscoring its potential as a therapeutic target(Gong, Huang, Shi, Liang, & Bu, 2023; W. Sun et al., 2023).
In our study, we explored the interplay between PANoptosis and the tumor microenvironment (TME), with a particular focus on TAMs(Gao et al., 2024). TAMs are key regulators of the TME, exhibiting both pro-tumorigenic and anti-tumorigenic functions depending on their polarization state(Vitale, Manic, Coussens, Kroemer, & Galluzzi, 2019). We hypothesized that the modulation of PANoptosis in TAMs could influence tumor progression and therapeutic responses in sarcoma.
Our analysis revealed a set of genes associated with macrophages within the sarcoma microenvironment, which intersected with PANoptosis-related genes. This finding suggests a potential crosstalk between PANoptosis and macrophage biology in sarcoma. Functional enrichment analysis further elucidated the roles of these genes in cytokine production, inflammatory responses, and immune regulation, underscoring their importance in shaping the TME.
Building on these findings, we developed a prognostic model based on the expression of PANoptosis and macrophage-associated genes. The model demonstrated robust predictive power across multiple datasets, highlighting its potential clinical utility in stratifying sarcoma patients based on their risk profile. Furthermore, mutation analysis revealed associations between specific TP53 mutations and the risk model, providing insights into the genetic landscape of sarcoma and its impact on disease progression. GSEA and GSVA outcomes indicated that samples with lower risk propensity tend to engage in multiple immune-related processes and inflammatory response. The inverse correlation observed between the majority of immune cells and the risk-score suggests that samples with a lower risk exhibit a more robust immune response to the immunological microenvironment of sarcoma, thereby contributing to a more favorable prognosis. Additionally, individuals in the two distinct risk groups demonstrated varying half-maximal inhibitory concentrations (IC50s) for different therapeutic drugs and distinct responses to immunotherapy. This underscores the potential of this risk model to customize more personalized therapy for sarcoma patients.
Leveraging these insights, we successfully constructed stable knockdown models of UNC5B within 143B cell lines. However, the sole knockdown of UNC5B did not yield a significant impact on the proliferation of 143B cells. Intriguingly, UNC5B knockdown yielded palpable reductions in osteosarcoma cell proliferation and migration, while also curbing their anti-apoptotic tendencies after facing paclitaxel treatment. Further experimental studies found that UNC5B knockdown made sarcoma cells more susceptible to immunogenic cell death when treated with paclitaxel. These findings shed new light on the intricate crosstalk between PANoptosis and macrophages within the tumor immune microenvironment, offering novel insights into potential therapeutic strategies for cancer treatment.
Overall, our study deepens the understanding of the molecular mechanisms underlying sarcoma pathogenesis and offers insights into potential therapeutic targets and personalized treatment approaches. By elucidating the interplay between PANoptosis, macrophages, and the TME, we offer a novel framework for unraveling the complexities of sarcoma biology and advancing precision oncology strategies for improved patient outcomes. Despite the promising predictive capacity of the prognostic signature predicated and its potential for personalized treatment modalities in sarcoma patients, the study underscores the imperative for broader cohort studies owing to the limited sample size available.