Search Results (2,038)

Leiomyosarcoma (LMS) is a rare, aggressive soft-tissue sarcoma arising from smooth muscle cells. It has a high metastatic potential and limited therapeutic options. Despite advances in oncology, the molecular landscape of LMS remains incompletely understood, particularly regarding the genetic and epigenetic alterations that affect key signaling pathways. This review summarizes the current knowledge of mechanisms driving LMS pathogenesis, including somatic mutations in genes such as TP53 and RB1, chromosomal instability, dysfunction of DNA damage response and repair, aberrant DNA methylation, histone modifications, and non-coding RNAs. Emerging treatment strategies include inhibitors of PI3K/AKT/mTOR and CDK4/6 signaling, epigenetic drugs, immunotherapy, and combinations of these approaches. However, the coexistence of multiple genetic abnormalities complicates diagnosis, prognosis, and therapeutic selection. Companion diagnostic tools that test candidate therapies ex vivo or in vitro may help exclude potentially ineffective targeted treatments. Full article

Background: Herein, we report on the development of a novel submicron-sized formulation that utilizes the somatostatin receptor agonist, octreotide (OCT), for the solubilization and targeted delivery of paclitaxel (PTX) and docetaxel (DTX) to the cancer cells. The formulation was prepared using a fast, single-step, and scalable method, and then, it was characterized in terms of physicochemical properties and pharmacological activities. Methods: Formulation analyses by Electrospray Ionization Mass Spectrometry (ESI-MS) and High-Performance Liquid Chromatography (HPLC) confirmed the successful formation of the formulation and the inclusion of all of its components. Results: Meanwhile, the developed formulation showed acceptable physicochemical properties with no incompatibilities among its components. In addition, the prepared formulation, OCT-PTX-DTX, demonstrated superior anticancer activities against colorectal carcinoma cell lines compared to the free drugs, with minimal effects on the normal cells. Furthermore, a synergistic anticancer activity of PTX and DTX was enabled by the novel formulation, leading to cell cycle arrest at low drug concentrations. Conclusions: Molecular-based mechanistic investigations verified that OCT-PTX-DTX is taken up by colorectal cancer cells via somatostatin receptors 1 and 2 (SSTR1 and SSTR2), followed by the upregulation of the tumor-suppressor p53/p21 cascade, and the induced cell cycle arrest via suppression of the cell cycle drivers CDK2 and Cyclin A. The formulation reported herein is promising for targeted and biotolerable anticancer chemotherapy compared to the commercially available taxane formulations based on surfactants or organic solvents. Full article

Metastatic breast cancer (MBC) remains incurable because of tumor evolution. Despite advances in targeted therapies—CDK4/6 inhibitors, PIK3 inhibitors, HER2-directed agents, and antibody–drug conjugates—median overall survival is modest, with resistance emerging in nearly all patients. From an evolutionary perspective, standard continuous maximum tolerated dose (MTD) therapy may create intense selective pressure that reduces treatment-sensitive cells and, in some incurable and resistance-prone settings, could permit competitive release of resistant clones. While MTD remains the guideline-endorsed standard of care in many metastatic settings and has produced substantial survival gains, the eco-evolutionary framework highlights a potential trade-off rather than a categorical failure of MTD. Cancer is not just a genetic disease but an evolving ecosystem where cell populations compete for limited resources. Resistant cells typically carry a fitness cost—slower growth in the absence of treatment—creating an exploitable vulnerability. By preserving treatment-sensitive cells through dose modulation or treatment holidays (adaptive therapy), we can harness competitive suppression to control resistant populations and prolong disease control, potentially doubling time to progression compared to continuous MTD. This primer translates these ideas into plain language for clinical trial application. We explain four core eco-evolutionary principles every breast oncologist should know, review emerging evidence from adaptive therapy trials in breast and other cancers, and discuss practical implementation strategies to incorporate into future trials. The goal is not cure through eradication, but long-term control through evolutionary management. These evolution-informed strategies may, in selected contexts, help delay resistance and prolong disease control, and represent a complementary framework that warrants prospective testing. Full article

NOS1AP (CAPON) is a signaling adaptor implicated in glioblastoma (GBM) proliferation, but its chemical tractability remains largely unexplored. Here, affinity selection–mass spectrometry screening of 10,000 drug-like compounds identified NGM1, a small molecule scaffold that directly binds NOS1AP. Binding was confirmed by microscale thermophoresis (MST), yielding a dissociation constant of 11.9 ± 7.0 μM. Focused structure–activity analysis and molecular modeling identified structural features associated with NOS1AP recognition and provided a framework for compound optimization. In living cells, NGM1 produced a concentration-dependent reduction in the NanoBRET signal generated by the NOS1AP-NOS1 reporter pair, consistent with perturbation of the complex. NGM1 reduced viability in U87 and U251 GBM cells, with IC₅₀ values of 12.7 ± 0.91 and 17.3 ± 1.04 μM, respectively, while normal human astrocyte viability remained above 50% at 150 μM. Mechanistic studies in U87 cells demonstrated reduced DNA synthesis, G₀/G₁ cell-cycle accumulation, and induction of apoptosis, accompanied by increased p53 and CDKN1A and decreased CDK6. Collectively, these findings establish the initial chemical tractability of NOS1AP and identify NGM1 as a chemical scaffold for investigating NOS1AP-associated signaling in GBM. The findings also provide a foundation for optimizing NOS1AP-directed compounds. Full article

Inocutis levis (I. levis) is a rare edible and medicinal macrofungus with a traditional history of consumption as a dietary supplement and functional food raw material. However, the material basis and molecular mechanisms underlying its anti-breast cancer activity remain unclear. The present work aimed to systematically investigate the anti-proliferative activity of WYS, an active mycelial fraction isolated from I. levis, against MCF-7 breast cancer cells and to explore its underlying mechanisms. Firstly, 152 metabolites were putatively annotated in the WYS fraction via ultra-performance liquid chromatography–quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) combined with database matching. Through an integrated strategy combining network pharmacology and multi-algorithm machine learning screening, four core metabolites (dihydroartemisinin, cortisol, cinnamic acid, and guanosine) and five hub targets (CDK1, EGFR, TOP2A, FGF2, and KIT) were prioritized. Furthermore, 100 ns molecular dynamics simulations and molecular docking predicted favorable binding affinities between the core metabolites and their cognate target proteins and predicted that the anti-breast cancer effect of WYS may be associated with the regulation of cell cycle progression, mitochondrial apoptosis, and the MAPK signaling pathway. Subsequent in vitro functional assays validated that WYS inhibited the proliferation of MCF-7 cells in both dose- and time-dependent fashions, triggered G2/M phase arrest and intrinsic mitochondrial apoptosis, and inhibited the EGFR/MEK/ERK signaling axis, exhibiting limited cytotoxicity toward normal HUVEC cells. In vivo, WYS dose-dependently attenuated xenograft tumor growth, and its modulatory effects on cell cycle, apoptosis, and related signaling pathways were consistent with the in vitro observations. This study provides the first evidence that I. levis mycelial fraction WYS modulates EGFR/MEK/ERK-related signaling and induces G2/M cell cycle arrest, thereby exerting anti-proliferative and pro-apoptotic effects on MCF-7 breast cancer cells, providing a scientific basis for further investigation of I. levis as a functional food. Full article

The hepatocyte growth factor (HGF)/c-Met signaling pathway plays a central role in cellular proliferation, survival, migration, invasion, angiogenesis, and therapeutic resistance. Aberrant c-Met activation, driven by gene amplification, overexpression, activating mutations, exon 14-skipping alterations, or ligand-dependent stimulation, drives the development and progression of many solid tumors, positioning c-Met as a key target for anticancer drug development. The clinical effectiveness of c-Met-targeted treatments such as crizotinib, capmatinib, tepotinib, savolitinib, and cabozantinib has confirmed c-Met as a viable oncogenic driver for therapy, leading to the development of various next-generation inhibitors with different structures. This review provides a comprehensive perspective on small-molecule c-Met inhibitors from the perspectives of medicinal chemistry and structure-based drug design, encompassing approved drugs, investigational agents, natural-product-inspired leads, and emerging multitarget anticancer therapeutics. Particular emphasis is given to the principles of molecular recognition that govern c-Met inhibition. This includes the structure of the kinase domain, interactions at the ATP-binding site, recognition of the hinge region, and the different binding modes of Type I, Type II, and allosteric inhibitors. The design, synthesis, biological evaluation, and structure–activity relationships of diverse heterocyclic scaffolds that have shaped c-Met inhibitor discovery are critically analyzed. Key medicinal chemistry strategies, including scaffold hopping, bioisosteric replacement, conformational optimization, molecular hybridization, and multitarget pharmacophore integration, are discussed in the context of potency, selectivity, resistance management, and drug-like properties. Particular attention is given to the integration of structural biology, molecular docking, binding-mode analysis, and structure-guided optimization approaches that have enabled the development of potent c-Met-directed inhibitors. In addition, recent advances in dual- and multitarget agents that simultaneously modulate c-Met and complementary therapeutic targets, including VEGFR-2, EGFR, AXL, MER, PARP1, CDK2, and tubulin, are highlighted as promising strategies for overcoming pathway redundancy and acquired resistance. This review summarizes contemporary structure-based and medicinal chemistry principles underlying c-Met inhibitor discovery, critically evaluates the relationship between biochemical potency and therapeutic efficacy, and provides a framework for the rational design of next-generation c-Met-targeted and multitarget anticancer agents. Full article

Cirsium japonicum is a medicinal plant traditionally used in East Asian medicine and contains multiple bioactive constituents with potential anticancer properties. This review critically evaluates the anticancer effects of C. japonicum and its associated constituents within the Hallmarks of Cancer framework. Evidence was classified as direct plant-specific evidence, constituent-based evidence, or contextual mechanistic evidence to distinguish findings obtained using botanical preparations from those generated using purified compounds derived from other sources. Direct studies of C. japonicum extracts, flavonoid fractions, phenylpropanoid glycosides, and C. japonicum var. maackii-mediated gold nanoparticles demonstrate antitumor, cytotoxic, antiangiogenic, immunomodulatory, and ferroptosis-associated activities, although target-level validation remains limited. Among its associated constituents, pectolinarigenin has the most developed mechanistic evidence, involving RRM2–CDK1, TOP2A, STAT3, and PI3K/AKT/mTOR signaling. Apigenin, luteolin, acacetin, linarin, cirsimaritin, and pectolinarin additionally influence regulated cell death, proliferative signaling, angiogenesis, metastasis, immune regulation, metabolic vulnerability, senescence, and therapy response. However, much of this evidence relies on pathway-associated changes rather than direct target engagement or genetic validation. Furthermore, the pharmacokinetics, systemic exposure, botanical standardization, tumor selectivity, and clinical relevance of these compounds remain insufficiently characterized. Future studies should prioritize standardized preparations, quantitative exposure analysis, functional target validation, clinically relevant models, and carefully designed combination strategies. Collectively, C. japonicum provides a promising multi-hallmark framework for anticancer investigation, but substantial translational evidence is still required before its therapeutic potential can be established. Full article

Background/Objectives: In metastatic breast cancer (MBC) treated with CDK4/6 inhibitors, baseline neutrophil-to-lymphocyte ratio (NLR) is an established prognostic marker. On-treatment NLR dynamics have shown inconsistent associations with survival, and no prior study has applied a dominant-driver decomposition to classify patients by whether NLR change is neutrophil- or lymphocyte-driven. Methods: We retrospectively analyzed 352 patients with HR+/HER2− MBC treated with ribociclib. Using paired neutrophil and lymphocyte counts at baseline and at approximately 12 weeks (before cycle 4), a log-linear decomposition classified patients into four NLR-trajectory phenotypes by the dominant driver of change. Associations with progression-free survival (PFS) and overall survival (OS) were assessed using a 4-month landmark approach with multivariable Cox models, with consistency evaluated across four thresholds, tertiles, and a continuous model. Secondarily, NLR change was compared across five response-trajectory groups. Results: NLR trajectory was not associated with PFS in any specification (multivariable hazard ratio [HR] 1.15 per standard deviation [SD], 95% CI 0.97–1.37, p = 0.12) but was independently associated with OS (HR 1.40 per SD, 95% CI 1.18–1.67, p < 0.001), confirmed on bootstrap resampling. Adding NLR trajectory improved discrimination (C-index +0.04) and fit (likelihood-ratio p < 0.001). The OS effect was time-varying, attenuating beyond 24 months. NLR trajectory was unrelated to dose-limiting neutropenia (p = 0.58) or dose reduction (p = 0.69). Primary refractory patients showed blunted NLR decline versus responding or stable patients (p = 0.005), independent of baseline NLR. Conclusions: On-treatment NLR trajectory is a correlate of OS, independent of PFS, dose-limiting neutropenia, and dose reduction, in ribociclib-treated MBC, distinct from direct tumor control. Prospective validation is warranted. Full article

Background/Objectives: Tarin exhibits immunomodulatory and antiproliferative properties against several tumor cell lines. Nano-encapsulation in liposomes enhances its therapeutic potential by improving protein stability, bioavailability, and sustained release. Previous studies demonstrated that nano-encapsulated tarin induces cell cycle arrest, migration inhibition, apoptosis, and autophagy in triple-negative breast cancer cells; however, the molecular mechanisms underlying these effects remain poorly understood. To investigate the proteomic response elicited by nano-encapsulated tarin, MDA-MB-231 cells were treated for 24 and 48 h. Methods: Intracellular proteins were extracted, digested with trypsin, and analyzed by label-free LC-2D-MS/MS using HDMSE acquisition. Differentially expressed proteins were identified and quantified using the Progenesis QI platform, and then functional classification and pathway enrichment analyses were performed. Results: A total of 2818 proteins were identified, of which 2150 displayed time-dependent modulation following treatment. After 24 h, cells exhibited an adaptive stress response profile characterized by increased DNA repair proteins (CHEK1, CDK12), migration/remodeling factors (LAMA4, CTTN, A2M), and immune/cell cycle regulators (PER2, HLA-B), while antioxidant proteins (SOD1, GPX1) and BRCA1 were reduced, indicating oxidative stress and DNA damage. After 48 h, the proteomic profile shifted toward cell death, with increased PARK7, OPA1, ATL3, and CASP8 expression, disruption of DNA repair and cell cycle regulators (CHEK1, CDK12, MSH6, KIF2C), and decreased migration-related proteins (LAMA4, CTTN, ITGB3, A2M). Conclusions: Nano-encapsulated tarin promotes a time-dependent transition from early adaptive stress responses to apoptosis, autophagy, cell cycle disruption, and loss of migratory capacity. These findings provide novel insights into the molecular mechanisms underlying tarin antitumoral activity and support its potential as a promising therapeutic strategy against triple-negative breast cancer. Full article

Oral squamous cell carcinoma (OSCC) remains a clinically challenging malignancy because of recurrence, treatment resistance, and limited therapeutic efficacy in advanced disease. This study investigated the anticancer effects and molecular mechanisms of jaceidin (JAC), a naturally occurring flavonoid derivative, in human OSCC cells. SCC-1 and SCC-47 cells were treated with JAC, and cell viability, colony formation, cell cycle distribution, apoptosis, and apoptosis-related signaling pathways were examined. JAC reduced OSCC cell viability and colony formation in a dose- and time-dependent manner. It also induced G2/M cell cycle accumulation and decreased the expression of cyclin D1, cyclin E1, phosphorylated cdc2, and CDK2/4/6. Apoptosis analyses showed that JAC promoted caspase-dependent apoptotic signaling, as evidenced by increased cleavage of caspase-3, caspase-8, caspase-9, and PARP. JAC modulated death receptor-associated signaling, characterized by increased Fas, TRADD, and DR5 expression and caspase-8 cleavage, while the decoy receptors DcR2 and DcR3 were also upregulated. JAC also promoted mitochondrial apoptotic signaling by increasing Bax, Bak, and Bim expression while decreasing Mcl-1. In addition, JAC attenuated AKT and ERK1/2 phosphorylation, and pharmacological inhibition with LY294002 or U0126 further enhanced JAC-induced apoptotic signaling. Furthermore, JAC reduced survivin expression and attenuated survivin-mediated apoptotic resistance. These findings suggest that JAC suppresses OSCC cell survival in association with modulation of AKT/ERK–survivin signaling and caspase-dependent apoptosis. Full article

Background/Objectives: The prognostic nutritional index (PNI) has been associated with outcome in metastatic breast cancer, but studies in CDK4/6 inhibitor-treated patients have used cohort-derived thresholds and examined only the pretreatment value. We assessed the PNI as a continuous variable, compared it with inflammatory indices, and examined whether repeated measurement added information. Methods: We reviewed 192 consecutive patients with hormone receptor–positive, HER2-negative metastatic breast cancer treated with a CDK4/6 inhibitor and endocrine therapy at a single centre. We calculated the PNI, neutrophil-to-lymphocyte ratio (NLR), and systemic inflammation response index (SIRI) before treatment and recalculated them before cycles 2 and 3. The Cox models were adjusted for age, liver metastasis and line of therapy; no threshold was derived from these data. Results: The median follow-up was 44.9 months. Each one-point increase in the baseline PNI was independently associated with lower hazards of progression (HR 0.952, 95% CI 0.923–0.983) and death (HR 0.919, 95% CI 0.884–0.956), corresponding to HR 0.782 (95% CI 0.670–0.918) and HR 0.656 (95% CI 0.540–0.799) per five-point increase. For overall survival, in formal comparisons on identical patient sets, neither the NLR nor the SIRI added prognostic information to a model containing the PNI (likelihood ratio p = 0.383 and p = 0.335), whereas the PNI added information to models containing either ratio (p < 0.001 and p = 0.004). In exploratory landmark analyses, change in the PNI added little to the baseline value; apparent associations between increases in the NLR or SIRI by cycle 3 and overall survival did not persist after winsorisation of extreme change scores. Conclusions: Baseline PNI, analysed as a continuous variable and without a data-derived threshold, was independently associated with progression-free and overall survival in this cohort. For overall survival, neither baseline inflammatory ratio added detectable prognostic information beyond the index, and repeated measurement during treatment added little to the baseline value, although the confidence intervals do not exclude modest effects. Because all patients received a CDK4/6 inhibitor and no comparator arm was available, these findings support a prognostic rather than a predictive interpretation, and external validation is required before the index can inform clinical decisions. Full article

Background: Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma that is histologically and clinically heterogeneous. Skeletonization is a computer vision technique used in image description, segmentation, and pattern recognition. Objectives: This retrospective observational study analyzed the 2D-topological heterogeneity of DLBCL. Methods: A series of 153 patients, including 110 patients with DLBCL and 43 patients with reactive lymphoid tissue, were analyzed by skeleton analysis using hematoxylin and eosin (H&E) digitized images. The skeletonization variable was correlated with several clinicopathological characteristics of the patients, including cell of origin Hans’ classifier and Lymph2Cx assay, MYC and BCL2 rearrangement by FISH, immunohistochemistry of BCL2, CASP8, cCASP3, CD163, CDK6, cPARP, CSF1R, E2F1, ISY1, Ki69, LMO2, MDM2, MYC, MYO, TNFAIP8, PD-L1, and p53, and gene expression using a pancancer immune profiling panel. Results: In comparison with reactive tissue, DLBCL was characterized by lower skeletonization: 5665.20 ± 1012.82 vs. 6341.16 ± 548.23, respectively (p < 0.001). Within the DLBCL diagnostic category, high skeletonization correlated with poor overall survival (hazard risk = 2.5, p = 0.003). High skeletonization was also correlated with higher Epstein–Barr virus (EBV) EBER positivity, death within the first two years, high histological entropy, and lower CD5, E2F1, BCL2, ISY1, and TNFAIP8 protein levels (all p values < 0.05). Gene expression was available in a representative subset of 30 cases, including 18 cases with high skeletonization and 12 cases with low skeletonization. High skeletonization was characterized by upregulation of 166 immuno-oncology genes, such as CD274 (PD-L1), NFKB1A, CD68, CSF1R, CCR5, ITGAM, and TGFB1, and enrichment of IL6 JAK STAT3 signaling, inflammatory response, TNF, NFKB, KRAS, apoptosis, and macrophage function pathways by gene set enrichment analysis (GSEA). In multivariate COX regression analysis for overall survival, the prediction value of skeletonization was independent of Hans’ classifier, the International Prognostic Index (IPI), and EBER (p = 0.030, hazard risk = 2.2). Conclusions: DLBCL is characterized by lower skeletonization than reactive lymphoid tissue. In DLBCL, high skeletonization is associated with poor prognosis and enrichment of immuno-oncology markers. Full article

Cancer remains a major global health concern, driving the search for safe and effective bioactive compounds from natural sources. Jujube peel red pigment (JP), an anthocyanin-rich extract, has shown preliminary bioactivity, yet its antitumor potential and delivery challenges remain underexplored. This study systematically evaluated the in vitro antitumor activity of JP and developed a thermosensitive hydrogel-based local delivery system (JP-H) to overcome its rapid diffusion and poor retention. JP exhibited selective cytotoxicity against HeLa cervical cancer and B16 melanoma cells, with no obvious toxicity to normal L929 and RAW264.7 cells. In HeLa cells, JP exerted antitumor effects by initiating mitochondrial-dependent apoptosis accompanied by elevated expression of Bax and cleaved Caspase-9/-3 as well as decreased Bcl-2 level, and arrested cell cycle at the G1/S phase by regulating CCND1, CDK2, CDK4, PCNA, MYC and TP53. To enable localized delivery, JP was incorporated into an injectable chitosan/gelatin/F127 thermosensitive hydrogel (JP-H), which exhibited rapid sol-gel transition at physiological temperature, shear-thinning behavior, and a porous microstructure. JP-H not only sustained JP release but also significantly enhanced antibacterial activity against E. coli and S. aureus compared to free JP. Furthermore, JP-H markedly inhibited HeLa cell migration and induced superior apoptotic/necrotic cell death in co-culture assays, outperforming free JP. Collectively, this work establishes JP as a multi-target antitumor agent and demonstrates JP-H as a promising local therapeutic platform combining sustained delivery, antibacterial protection, and enhanced anticancer efficacy for cervical cancer treatment. Full article

Background: Solid tumors including glioblastoma (GBM), lung cancer (LC), and triple-negative breast cancer (TNBC) exhibit marked radioresistance driven by dysregulated cell-cycle control and genomic instability. Although CDK4/6 inhibitors suppress tumor proliferation, their radiosensitizing capacity is limited by persistent DNA repair. BUB1, a mitotic checkpoint kinase overexpressed in aggressive cancers, has emerged as a regulator of DNA damage signaling. We tested whether co-targeting BUB1 and CDK4/6 enhances radiosensitivity across solid tumors. Methods: GBM, LC, and TNBC cell lines were treated with BUB1 inhibitor BAY1816032, CDK4/6 inhibitors ribociclib and abemaciclib, and radiation. Proliferation, clonogenic survival, immunoblotting, and combination index analyses assessed cytotoxicity and synergy. CDK4/6-resistant models were generated to examine resistance. In vivo efficacy was evaluated using SUM159 xenografts. DNA damage and homologous recombination repair were measured by gH2AX, RAD51, RPA, BrdU foci and comet assay. The resection branchpoint was assessed by phospho-RPA, with ATR inhibition and BLM or EXO1 depletion testing resection dependence. Results: BUB1 inhibition increased cytotoxicity in vitro and improved therapeutic response in vivo. Combined BUB1 and CDK4/6 inhibition showed strong synergy (C.I. < 1) and enhanced radiosensitization in RB+ models. CDK4/6-resistant cells displayed increased BUB1 expression, and BUB1 inhibition partially restored sensitivity. Mechanistically, dual inhibition intensified homologous recombination defects, marked by persistent gH2AX and altered RAD51, RPA, and BrdU dynamics, consistent with sustained single stranded DNA and impaired HR repair. Persistent RPA32 Ser33 phosphorylation reflects ATR-dependent resection that requires BLM and EXO1 at later stages, supporting sustained resection and unresolved repair leading to increased cell death. Conclusions: Dual inhibition of BUB1 and CDK4/6 represents a promising therapeutic strategy for enhancing radiosensitivity in GBM, lung cancer, and TNBC, particularly in Rb-intact settings. Full article

PIK3CA, which encodes the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K), is one of the most frequently altered oncogenes in human cancer and a major driver of tumor initiation, progression, metastasis, and therapeutic resistance. Over the past two decades, advances in structural biology, cancer genomics, and translational research have substantially expanded our understanding of PIK3CA function and established the PI3K pathway as a clinically actionable therapeutic target. This review provides an overview of the structural organization and physiological functions of the PI3Kα complex, the molecular mechanisms underlying oncogenic activation, and the diverse spectrum of PIK3CA alterations across human malignancies. We also summarize the current landscape of PI3K-targeted therapies, highlighting both approved agents and emerging therapeutic strategies. Clinical evidence supports the rational integration of PI3K inhibitors with endocrine therapy, CDK4/6 inhibitors, MAPK pathway inhibitors, dual PI3K/mTOR inhibition, and immune checkpoint blockade. In addition, accumulating evidence indicates that PIK3CA plays a pivotal role in shaping the tumor immune microenvironment, providing a biological rationale for combining PI3K inhibition with immunotherapy. Finally, we discuss future directions in precision oncology, emphasizing integrated molecular profiling, liquid biopsy, single-cell and spatial technologies, functional genomics, and evolutionary approaches as complementary strategies to refine patient selection, overcome therapeutic resistance, and optimize clinical outcomes. Full article