T helper (Th) cells have received extensive attention owing to their indispensable roles in anti-tumor immune responses. Th1 and Th2 cells are two key subsets of Th cells that exist in relative equilibrium through the secretion of cytokines that suppress their respective immune response. When the type of cytokine in the tumor microenvironment is altered, this equilibrium may be disrupted, leading to a shift from Th1 to Th2 immune response. Th1/Th2 imbalance is one of the decisive factors in the development of malignant tumors. Therefore, focusing on the balance of Th1/Th2 anti-tumor immune responses may enable future breakthroughs in cancer immunotherapy. Polysaccharides can regulate the imbalance between Th1 and Th2 cells and their characteristic cytokine profiles, thereby improving the tumor immune microenvironment. To our knowledge, this study is the most comprehensive assessment of the regulation of the tumor Th1/Th2 balance by polysaccharides. Herein, we systematically summarized the intrinsic molecular mechanisms of polysaccharides in the regulation of Th1 and Th2 cells to provide a new perspective and potential target drugs for improved anti-tumor immunity and delayed tumor progression.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway serves as an immune sentinel for cytosolic DNA, recognizing double-stranded DNA (dsDNA) derived from abnormally localized nuclear DNA or mitochondrial DNA (mtDNA), and plays a pivotal role in innate immune responses and tumor immune surveillance. Conventional antitumor therapies induce genomic instability and mitochondrial stress, leading to the release of nuclear DNA and mtDNA into the cytosol, thereby activating the cGAS-STING pathway. This activation triggers the production of type I interferons (IFN-I) and pro-inflammatory cytokines, which reshape the tumor immune microenvironment (TIME). However, the complexity of TIME reveals a “double-edged sword” effect of cGAS-STING signaling: while it activates antitumor immune responses, it also promotes immune escape and metastasis through the regulation of immunosuppressive cells and stromal components. This review comprehensively delineates the differential regulatory mechanisms of the pathway within TIME constituents, highlighting its multifaceted roles in tumor immunity. Furthermore, it reviews recent advances and challenges in targeting the cGAS-STING pathway for cancer immunotherapy, with the aim of advancing cGAS-STING signaling modulation as a key therapeutic strategy to reprogram TIME and overcome immunosuppression in antitumor treatment.

Cryptotanshinone (IUPAC name: (R)-1,2,6,7,8,9-hexahydro-1,6,6-trimethyl-phenanthro(1,2-b)furan-10,11-dione), a biologically active constituent extracted from the roots and rhizomes of the plant Salvia miltiorrhiza, has been studied in depth as a medicinally active compound and shown to have efficacy in the treatment of numerous diseases and disorders. In this review, we describe in detail the current status of cryptotanshinone research, including findings relating to the structure, pharmacokinetics, pharmacological activity, and derivatives of this compound. Cryptotanshinoneh as a diverse range of pharmacological effects, including anti-cancer, anti-inflammatory, immune regulatory, neuroprotective, and anti-fibrosis activities. Studies on the molecular mechanisms underlying the activities of cryptotanshinone have established that the JAK2/STAT3, PI3K/AKT, NF-κB, AMPK, and cell cycle pathways are involved in the inhibitory and pro-apoptotic effects of cryptotanshinone on different tumor cell lines, these molecular pathways interact in a coordinated manner to inhibit cell proliferation, migration and invasion,and induce transformation, autophagy, necrosis, and cellular immunity. The anti-inflammatory mechanisms of cryptotanshinone have been found to be associated with the TLR4-MyD88/PI3K/Nrf2 and TLR4-MyD88/NF-κB/MAPK pathways, whereasthe Hedgehog, NF-κB, and Nrf-2/HO-1 pathways are regulated by cryptotanshinone to reduce organ fibrosis, and its inhibitory effects on the PI3K/AKT-eNOS pathway have been linked to neuroprotective effects. Given the potential medicinal utility of cryptotanshinone, further research is needed to verify the efficacy and safety of this compound in clinical use, evaluate its pharmacological activity, and identify molecular targets.

Drug resistance is a common challenge in clinical tumor treatment. A reduction in drug sensitivity of tumor cells is often accompanied by an increase in autophagy levels, leading to autophagy-related resistance. The effectiveness of combining chemotherapy drugs with autophagy inducers/inhibitors has been widely confirmed, but the mechanisms are still unclear. Ferroptosis and pyroptosis can be affected by various types of autophagy. Therefore, ferroptosis and pyroptosis have crosstalk via autophagy, potentially leading to a switch in cell death types under certain conditions. As two forms of inflammatory programmed cell death, ferroptosis and pyroptosis have different effects on inflammation, and the cGAS-STING signaling pathway is also involved. Therefore, it also plays an important role in the progression of some chronic inflammatory diseases. This review discusses the relationship between autophagy, ferroptosis and pyroptosis, and attempts to uncover the reasons behind the evasion of tumor cell death and the nature of drug resistance.

The JAK-STAT signaling pathway is a common pathway of many cytokine signal transductions, closely related to cell proliferation, apoptosis, differentiation, and inflammatory response. It is essential for inhibiting the inflammatory response, initiating innate immunity, and coordinating adaptive immune mechanisms. Owing to the nature of this pathway and its potential cross-epitopes with multiple alternative pathways, the long-term efficacy of monotherapy-based adaptive targeting therapy is limited, and the majority of drugs targeting STATs are still in the preclinical phase. Meanwhile, curcumin, quercetin, and several kinds of plant polyphenol chemicals play roles in multiple sites of the JAK-STAT pathway to suppress abnormal activation. Polyphenol compounds have shown remarkable effects by acting on the JAK-STAT pathway in anti-inflammatory, antitumor, and cardiovascular disease control. This review summarizes the pharmacological effects of more than 20 kinds of phytochemicals on JAK-STAT signaling pathway according to the chemical structure of polyphenolic phytochemicals.