Novel therapeutic strategies are urgently needed for the treatment of colorectal cancer (CRC), which is the third most common cancer and the second leading cause of cancer-related mortality worldwide. Natural products are a pivotal source for the discovery of new anticancer agents. Oridonin (DLC) and its derivatives have demonstrated the ability to inhibit malignancy through regulating multiple pathways, presenting promising options for CRC therapy. In this work, we identified an DLC derivative, oridonin 13 (DLC13), which exhibited 11.5-fold and 4.8-fold greater potency against HCT116 and HT29 cell proliferation than DLC, and achieved equivalent tumor suppression in HCT116 xenografts at half the dosage. DLC13 effectively inhibited DNA damage repair, cell cycle progression, stemness, and migration of CRC cells. As a first-line chemotherapeutic agent for CRC, oxaliplatin (OXA) drives aberrant expression of genes involved in DNA damage repair, cell cycle progression, stemness, and migration, leading to the development of OXA resistance. DLC13 was shown to suppress the abnormal gene expression driven by OXA, indicating its potential to reverse OXA resistance. Indeed, we found that DLC13 and OXA synergistically inhibited the malignant proliferation of CRC cells, and DLC13 enhanced the sensitivity of OXA-resistant CRC cells to OXA treatment. Activity-based protein profiling (ABPP) proteomics identified proliferating cell nuclear antigen (PCNA), a critical regulator of DNA replication and repair, as a direct target of DLC13. Importantly, PCNA is a critical driver of OXA resistance in CRC. Further mechanistic studies revealed that DLC13 binds to the QSMDSSH motif of PCNA, facilitating its K48-linked polyubiquitination and subsequent proteasomal degradation, thereby inhibiting the biological function of PCNA. Knockdown of PCNA suppressed CRC cell proliferation, DNA damage repair, cell cycle progression, stemness, and migration, while restoring OXA sensitivity in resistant cells. In summary, PCNA is a direct target of DLC13. DLC13 inhibits malignant proliferation and reverses OXA resistance in CRC by promoting ubiquitination-dependent degradation of PCNA. The combination of oridonin derivatives with OXA may represent a promising approach for treating refractory CRC. Additionally, targeted inhibition of PCNA offers a potential approach to suppress CRC malignancy and overcome OXA resistance.

Protein acetylation is increasingly recognized as a key regulator of tumor progression, yet natural compounds capable of modulating this modification remain poorly defined. Apigenin, a dietary flavonoid suppresses bladder cancer progression based on in vitro functional assays and dynamic xenograft models. Mechanistically, we applied an integrated multi-omics approach to unravel that apigenin enhances SIRT6-mediated deacetylation of Nuclear Receptor Coactivator 2 (NCOA2), leading to site-specific deacetylation of NCOA2 at lysine 780 and 785. This modification potentiates PPARα transcriptional activity, reprograms cellular energy metabolism, and disrupts mitochondrial membrane potential. Clinically, reduced SIRT6 expression coupled with elevated NCOA2 and mitochondrial/β-oxidation markers correlates with metastatic progression in bladder cancer. Together, these findings identify a previously unrecognized SIRT6-NCOA2-PPARα signaling axis as a metabolic vulnerability in bladder cancer.

Chimeric antigen receptor (CAR) T cell therapy demonstrates suboptimal efficacy in T-cell acute lymphoblastic leukemia (T-ALL), largely due to target-mediated fratricide from shared antigen expression and effector T cell exhaustion. The Mucin1-Thomsen-nouvelle (MUC1-Tn) antigen is overexpressed in various malignancies, including T-ALL. In this study, we confirmed MUC1-Tn protein expression in T-ALL cell lines and primary patient-derived bone marrow cells and subsequently developed MUC1-Tn-targeted CAR T cells. These CAR T cells effectively lysed T-ALL cells in both in vitro cytotoxicity assays and xenograft models. Given the critical role of the PI3Kδ signaling pathway in modulating T-cell function and tumor immunosuppression, we combined MUC1-Tn CAR T cells with the PI3Kδ inhibitor linperlisib. Linperlisib enhanced the anti-leukemic efficacy and persistence of MUC1-Tn CAR T cells. This was associated with reduced T cell exhaustion marker expression, decreased proportions of terminally differentiated cells, and sustained tumor control upon rechallenge. Furthermore, linperlisib induced mitochondrial fusion and enhanced respiratory capacity in CAR T cells. Mechanistically, this enhanced persistence was attributed to linperlisib-mediated suppression of Dual Specificity Phosphatase 2 (DUSP2) and its upstream transcription factor Early Growth Response 1 (EGR1).

Regulatory T cells (Tregs) are central mediators of immune tolerance and key drivers of tumor immune evasion in non-small cell lung cancer (NSCLC). Within the tumor microenvironment (TME), Tregs accumulate and suppress antitumor responses, thereby limiting the durability of immune checkpoint inhibitor (ICI) responses. Emerging evidence indicates that Treg influence on immunotherapy outcomes extends beyond numerical abundance to involve a dynamic Treg-cell death axis, in which enhanced Treg survival and resistance to regulated cell death are coupled with dysfunction, exhaustion, or attrition of effector T cells. Tumor-derived chemokines, cytokines, and metabolic cues promote recruitment, stabilization, and metabolic fitness of Tregs, enabling their persistence within hypoxic and nutrient-deprived niches. Concurrently, Tregs suppress antigen-presenting cell activation, amplify checkpoint signaling, and exploit metabolic and redox adaptations including ferroptosis resistance to maintain immunosuppressive dominance under therapeutic pressure. Together, these mechanisms establish a survival-advantaged regulatory compartment that drives immune cell-fate asymmetry within the TME and limits the durability of immune checkpoint blockade. We propose the Treg-cell death axis as a unifying framework linking immune tolerance, regulated cell death, and immunotherapy resistance in lung cancer. Targeting this axis through mechanism-matched strategies that destabilize tumor-resident Tregs while preserving systemic immune homeostasis may provide new opportunities to overcome therapeutic resistance and improve clinical outcomes.

BACKGROUND:Multidrug resistance (MDR) in cancer is a major obstacle to achieving success in clinical chemotherapy. It has been observed that overexpression of ATP-Binding Cassette (ABC) transporters plays a crucial role in MDR. OBJECTIVE:This study aimed to find an effective resistance-reversed agent of ABC transporter. A series of new β-carboline derivatives have been synthesized and are being applied in various invention patents. One of these is B-9-8, a novel harman dimer, which was synthesized to conduct a series of experiments. METHODS:In this study, we investigated whether B-9-8 could reverse ABCG2-mediated drug resistance by using MTT assay, [3H]-mitoxantrone accumulation/efflux assay, western blot analysis, immunofluorescence analysis, ATPase assay, and molecular modeling assay. RESULTS:The results showed that B-9-8 could significantly increase the sensitivity to mitoxantrone, SN-38, and topotecan and effectively overcame drug resistance at non-toxic concentrations in ABCG2-overexpressing cells. Further studies showed that B-9-8 increased the intracellular accumulation of [3H]-mitoxantrone by suppressing the efflux function of ABCG2 in ABCG2- overexpressing cells. B-9-8 could down-regulate the ABCG2 protein expression but did not change the subcellular localization of ABCG2. ATPase analysis indicated that B-9-8 inhibited the ATPase activity of ABCG2 in a concentration-dependent manner. In the molecular docking analysis, B-9-8 demonstrated a strong interaction with the human ABCG2 transporter protein. DISCUSSION:B-9-8, as a novel harman dimer, exhibits its reversal activity against ABCG2- mediated multidrug resistance without obvious cytotoxicity. Its actions of inhibiting ABCG2 efflux function and down-regulating the protein expression of ABCG2 are crucial for overcoming drug resistance. This makes B-9-8 a possible candidate drug for combined chemotherapy. Its inhibitory effect of ATPase activity and the strong affinity to ABCG2 further demonstrate the potential of B-9-8 as a targeted modulator for drug resistance. CONCLUSION:Our findings indicated that B-9-8 could reverse ABCG2-mediated MDR as a potential and reversible modulator in combination with conventional chemotherapeutic drugs.

Abstract Background The lack of effective biomarkers and therapeutic targets to overcome radioresistance in cervical cancer remains a major clinical challenge. Tumor necrosis factor receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase pivotal in immune and inflammatory signaling, has been implicated in various malignancies. However, its role in radioresistance in cervical cancer remains unclear. Methods TRAF6 expression was evaluated in cervical cancer tissues from 162 patients who underwent postoperative radiotherapy at our institution and in 304 cases from the TCGA-CESC cohort. The prognostic significance of TRAF6 was assessed using Kaplan-Meier and Cox regression analyses. A nomogram integrating TRAF6 expression with clinicopathological factors was constructed to predict overall survival (OS) and progression-free survival (PFS). The functional role of TRAF6 in malignant phenotypes and radiosensitivity was investigated using shRNA-mediated knockdown in HeLa and C33A cervical cancer cells. Immune cell infiltration patterns associated with TRAF6 expression were analyzed using ssGSEA and xCELL algorithms based on TCGA data. Results TRAF6 expression was significantly elevated in cervical cancer tissues compared with adjacent normal tissues (70.99% vs. control, P < 0.001) and was higher in radioresistant than in radiosensitive patients ( P < 0.001). High TRAF6 expression was associated with shorter OS (HR = 18.73, P = 0.004) and PFS (HR = 8.44, P < 0.001) and was identified as an independent risk factor for radiotherapy resistance (OR = 8.44, P < 0.001). The TRAF6-integrated nomogram demonstrated good predictive accuracy for OS (C-index = 0.7351) and PFS (C-index = 0.7444). TRAF6 knockdown in cervical cancer cells significantly suppressed proliferation, migration, and invasion, while substantially enhancing radiosensitivity of tumor cells. Functional enrichment analysis revealed that TRAF6-related genes were enriched in autophagy, mitophagy, and HPV infection pathways. Immune cell infiltration analysis showed that TRAF6 expression correlated with distinct immune cell profiles, characterized by enrichment of activated dendritic cells, M1 macrophages, and regulatory T cells, alongside depletion of cytotoxic effectors such as CD8+ T cells and γδ T cells. Conclusions TRAF6 could be a prognostic biomarker associated with poor outcomes and indicator of radiotherapy resistance in cervical cancer, TRAF6 represents a potential therapeutic target for overcoming radioresistance in cervical cancer.

Endometrial cancer is one of the most prevalent malignancies of the female reproductive system, and the global rising prevalence of obesity has further increased its incidence and poor clinical prognosis. Although obesity is recognized as a critical modifiable risk factor for endometrial cancer, it remains unclear whether and how obesity drives tumor initiation and progression by modulating the tumor microenvironment at single-cell resolution. Using a genetic mouse model with pten conditional knockout in the uterine endometrium, clinical samples from endometrial cancer patients, and single-cell RNA sequencing from 10 endometrial tumor samples, we delineated a comprehensive single-cell atlas of endometroid endometrial cancer altered by obesity. The results reveal a unique SOX9+LGR5+ epithelial subpopulation exhibiting cancer stem cell features, which establishes an intratumoral estrogen-signaling circuit. Tumor-associated macrophages and NK/T cells undergo profound metabolic reprogramming toward pro-tumor and immunosuppressive phenotypes. Fibroblasts exhibit remarkable phenotypic and metabolic rewiring within a lipid-rich microenvironment, facilitating extracellular matrix remodeling. Emerging endothelial subsets drive angiogenesis and vascular dysfunction, fostering intratumoral hypoxia and cancer cell metastasis. These components engage in extensive intercellular crosstalk centered on tumor-associated macrophages, forming a self-reinforcing network that drives immunosuppression, stemness maintenance, cell migration, and aberrant angiogenesis. Our findings highlight that obesity-induced tumor microenvironment remodeling and metabolic communication constitute key mechanisms underlying tumor aggressiveness of obesity-related endometrial cancer, providing novel mechanistic insights and potential therapeutic targets for clinical intervention.

Paclitaxel resistance and poor tumor selectivity remain significant challenges in epithelial ovarian cancer therapy. To overcome these challenges, we engineered PSaA360, a structurally constrained aptamer-drug conjugate with a dual-functional molecular lock that simultaneously rigidifies the AS1411 aptamer and delivers potent telomerase inhibition. Unlike the conformational flexibility of conventional aptamer-drug conjugates, PSaA360 employs the G-quadruplex stabilizer 360A to simultaneously rigidify the AS1411 aptamer into a high-affinity conformation and deliver potent telomerase inhibition. This structure-constrained and therapy-integrated strategy improved nucleolin binding, enhanced cellular internalization, and counteracted paclitaxel chemoresistance. In vivo, PSaA360 exhibited marked tumor inhibition with minimal systemic toxicity. By transforming a therapeutic agent into a structural stabilizer, PSaA360 establishes a new paradigm for mechanism-guided aptamer engineering in chemotherapy-resistant malignancies.

G protein-coupled receptor 35 (GPR35), a member of the largest druggable gene family, has emerged as a critical regulator of tumor metabolism and immune modulation. Aberrant expression of GPR35 is frequently observed in digestive system malignancies and is associated with poor prognosis. This review comprehensively explores GPR35’s role in metabolic reprogramming, highlighting its regulatory functions in glucose, lipid, amino acid, and microbial metabolite metabolism. GPR35 shapes the tumor microenvironment through modulation of metabolite signaling, influencing angiogenesis, immune cell infiltration, and inflammation. It also acts as a key interface between host cells and the gut microbiota, contributing to cancer progression via microbial-derived metabolites. Pharmacological targeting of GPR35 shows promise, with several agonists and antagonists advancing through preclinical and early clinical development. However, challenges such as species-specific pharmacodynamics, ligand selectivity, and receptor isoform variability complicate drug development. Recent advances, including the creation of humanized GPR35 models, have facilitated translational research. Targeting GPR35-mediated metabolic reprogramming represents a novel therapeutic strategy, particularly for metabolically active digestive cancers. Future studies should focus on clarifying the metabolic pathways governed by GPR35 and optimizing receptor-specific therapeutics for clinical application.

Background: Colorectal adenoma represents the critical step in the development of colorectal cancer. The establishment of an immortalized epithelial cell line of colorectal adenoma of human origin would provide a tool for studying the mechanism of precancerous lesions, screening the efficacy of novel drugs, and constructing in vivo disease models. Currently, there is no commercially available stable supply of epithelial cells from precancerous lesions. Aims: This study aimed to establish a natural LHPP low-expressing precancerous epithelial cell line by SV40-LT antigen gene transfection. Methods: Simian vacuolating virus 40(SV40), SV40-LT overexpressed lentivirus vector, was transfected into primary human colorectal adenomatous polyp epithelial cells. The transfected cells were screened, and the screened cells were amplified to obtain the epithelial cell line: IHCRA- CELL. The cells were identified by morphological observation, cell proliferation, Quantitative real-time PCR (qPCR), and Short Tandem Repeats (STR) experiments. Morphologically, the cells showed epithelial-like characteristics, such as polygon shape, desmosomes mitochondria, and strong positive keratin staining. There was no significant difference between the transfected cells and the primary cells. Through the STR identification experiment, no matching cell lines were found in the cell lines retrieval. Conclusion: We successfully established a natural LHPP low-expressing precancerous epithelial cell line by SV40-LT antigen gene transfection, which has been patented and is now preserved in the Chinese Typical Culture Preservation Center. It was verified that the transformed cells maintained the phenotype and biological characteristics of epithelial cells. This cell line can be used to study the mechanism of precancerous lesions, screen the efficacy of novel drugs, and construct in vivo disease models.

Cancer evolution can engender tumours with the ability to resist multiple treatments with distinct chemical structures and mechanisms of action, and this multidrug resistance (MDR) phenotype has long been a substantial challenge in cancer therapy. Despite the established benefits of systemic treatments including chemotherapies, molecularly targeted therapies and immunotherapies across various cancers, MDR inevitably occurs at some point during the course of the disease and its treatment in most patients. Since the discovery of MDR in the 1960s, our understanding of the underlying mechanisms has deepened. However, few strategies are currently available to combat MDR in the clinical setting, and approaches to systematically translate knowledge of new MDR mechanisms and treatments from the laboratory into the clinic are lacking. In this Review, we focus on preclinical and clinical advances in understanding MDR, with an emphasis on resistance to chemotherapy and targeted therapy. We also summarize progress made in translating these findings from bench to bedside through the development of potential strategies to overcome MDR and thus improve patient outcomes. Despite advances in cancer therapy, the persistent challenge of treatment resistance and particularly multidrug resistance remains a substantial barrier to further improvements in patient outcomes. In this Review, the authors discuss preclinical and clinical advances in understanding multidrug resistance, with an emphasis on resistance to chemotherapies and targeted therapies, as well as the progress made in translating these findings into novel strategies to overcome this challenge and thus improve patient outcomes.

center dot Context.-Most patients with non-small cell lung cancers (NSCLC) are diagnosed at advanced stages. The 5year survival rate of patients with advanced lung cancer is less than 20%, which makes lung cancer the leading cause of cancer-related deaths worldwide. Objective.-To identify indicators that can predict the prognosis of lung cancer patients. Design.-To determine the correlation between circulating tumor cells (CTCs), circulating tumor-derived endothelial cells (CTECs), and their subtypes and the prognosis of patients with NSCLC, 80 patients with lung cancer were recruited and 48 patients who met the enrollment criteria were selected in this study. Peripheral blood was collected from the enrolled patients before any treatment and analyzed by the subtraction enrichment and immunostaining-fluorescence in situ hybridization technique to determine the correlation between CTCs and CTECs and lung cancer disease progression and to identify prognostic indicators. Results.-In all patients, the positive rate of CTCs was 100% and the positive rate of CTECs was 81.3%. Patients with advanced or lymph node metastases had a higher rate of small-size CTC positivity than those with early or no lymph node metastases. Large-size CTEC positivity was higher in patients with advanced NSCLC than in early-stage patients (P = .03). Patients with >= 1 small-size CTC had shorter progression-free survival, and it was an independent prognostic factor. Conclusions.-Small-size CTCs are a reliable prognostic indicator and a probable predictor of the severity of disease in NSCLC patients.

Non-small cell lung cancer (NSCLC) is acknowledged as the primary subtype of lung cancer. The Warburg effect, marked by elevated glucose consumption and lactate fermentation, is a prevalent characteristic of NSCLC. The mechanisms by which circRNA mediates the regulation of the Warburg effect and immune evasion in NSCLC remain unclear. This study found an elevated circRNA, circRUNX1, whiche promotes glycolysis and lactate generation, resulting in the infiltration of regulatory T cell (Treg) in NSCLC. circRUNX1 acts as a miR-145 sponge, inhibiting its negative regulation of the target gene HK2, therefore facilitating glycolysis and lactate generation. The accumulation of lactic acid in the tumor microenvironment promotes Treg cell proliferation and aids immune evasion. Functionally, the suppression of circRUNX1 significantly impedes tumor development both in vitro and in vivo. These findings collectively clarity a previously unexamined mechanism linking the circRUNX1/miR-145/HK2 axis in regulation of the Warburg effect and immune evasion in NSCLC.

Gastrointestinal cancer is one of the most prevalent malignant tumors worldwide. The treatment landscape of gastrointestinal cancer has entered a new era with the advent of immunotherapy, which activates the immune system to identify and eliminate tumor cells. Immunotherapy has demonstrated high efficacy and tolerable toxicity profiles compared to conventional therapies. Immune checkpoint inhibitors including PD-1, PD-L1, CTLA-4 and LAG-3 in combination with targeted therapy or chemotherapy have been approved for the treatment of gastrointestinal tumors with good clinical patient benefit. In recent years, a variety of novel immunotherapeutic approaches have emerged. For example, adoptive T-cell therapy, such as claudin18.2-targeted CAR-T has achieved an objective remission rate of 48.6% in patients with advanced gastric cancer and gastroesophageal junction cancer. Oncolytic viruses inhibits tumor growth in both tumor lysis and immune activation, and is currently showing its efficacy against gastrointestinal tumors in some clinical trials. In addition, cancer vaccines, with their unique high degree of precision, have improved the effectiveness of individualized therapy. Personalized neoantigen vaccines combined with other immunotherapeutic drugs or chemotherapy, have shown some efficacy and safety in gastrointestinal patients. In this review, we summarize these recent advances in immunotherapy for the treatment of gastrointestinal tumors. Additionally, the challenges and limitations linked to immunotherapy were explored. This review will expand our understanding of clinical studies on immunotherapy in gastrointestinal cancer and assist in individualizing patient treatment strategies, maximizing therapeutic benefits, and improving patient prognosis.

Multidrug resistance protein 7 (MRP7), also known as ATP-binding cassette (ABC) transporter subfamily C10 (ABCC10), is an ABC transporter that was first identified in 2001. ABCC10/MRP7 is a 171 kDa protein located on the basolateral membrane of cells. ABCC10/MRP7 consists of three transmembrane domains and two nucleotide binding domains. It mediates multidrug resistance of tumor cells to a variety of anticancer drugs by increasing drug efflux and results in reducing intracellular drug accumulation. The transport substrates of ABCC10/MRP7 include antineoplastic drugs such as taxanes, vinca alkaloids, and epothilone B, as well as endobiotics such as leukotriene C4 (LTC4) and estradiol 17 β-D-glucuronide. A variety of ABCC10/MRP7 inhibitors, including cepharanthine, imatinib, erlotinib, tariquidar, and sildenafil, can reverse ABCC10/MRP7-mediated MDR. Additionally, the presence or absence of ABCC10/MRP7 is also closely related to renal tubular dysfunction, obesity, and other diseases. In this review, we discuss: 1) Structure and functions of ABCC10/MRP7; 2) Known substrates and inhibitors of ABCC10/MRP7 and their potential therapeutic applications in cancer; and 3) Role of ABCC10/MRP7 in non-cancerous diseases.

Cancer cells frequently develop resistance to chemotherapeutic therapies and targeted drugs, which has been a significant challenge in cancer management. With the growing advances in technologies in isolation and identification of natural products, the potential of natural products in combating cancer multidrug resistance has received substantial attention. Importantly, natural products can impact multiple targets, which can be valuable in overcoming drug resistance from different perspectives. In the current review, we will describe the well-established mechanisms underlying multidrug resistance, and introduce natural products that could target these multidrug resistant mechanisms. Specifically, we will discuss natural compounds such as curcumin, resveratrol, baicalein, chrysin and more, and their potential roles in combating multidrug resistance. This review article aims to provide a systematic summary of recent advances of natural products in combating cancer drug resistance, and will provide rationales for novel drug discovery.

Over the past two decades, bioactivity-guided drug screening has become a pivotal approach in drug discovery, which could identify potential drug candidates with desirable therapeutic effects against specific disease phenotypes or targets. This strategy has led to the discovery of many clinical medications such as natural products, peptides, and antibody drugs, and become a mainstream method. Herein, we first systematically summarize the principles and applications of recent bioactivity-guided drug screening strategies through technological advances in in silico screening, cell model systems, organoid model systems, and animal model systems. We then provide an overview on the representative active compounds, pre-clinical drugs, and marketed drugs, and discuss the present challenges and future directions of bioactivity-guided drug screening methods for clinical drug development. Based on the research advancements, it is anticipated that more disease-relevant screening models and efficient methods can be developed to identify drugs with ideal therapeutic effects and favorable pharmacological properties.

Recent therapeutic strategies for the treatment of triple-negative breast cancer (TNBC) have shifted the focus from vascular growth factors to endothelial cell metabolism. This study highlights the underexplored therapeutic potential of peri-tumoral electroacupuncture, a globally accepted non-pharmacological intervention for TNBC, and molecular mechanisms. Our study showed that peri-tumoral electroacupuncture effectively reduced the density of microvasculature and enhanced vascular functionality in 4T1 breast cancer xenografts, with optimal effects on day 3 post-acupuncture. The timely integration of peri-tumoral electroacupuncture amplified the anti-tumor efficacy of paclitaxel. Multi-omics analysis revealed Glyoxalase 1 (Glo1) and the associated methylglyoxal-glycolytic pathway as key mediators of electroacupuncture-induced vascular normalization. Peri-tumoral electroacupuncture notably reduced Glo1 expression in the endothelial cells of 4T1 xenografts. Using an in vivo matrigel plug angiogenesis assay, we demonstrated that either Glo1 knockdown or electroacupuncture inhibited angiogenesis. In contrast, Glo1 overexpression increased blood vessel formation. In vitro pharmacological inhibition and genetic knockdown of Glo1 in human umbilical vein endothelial cells inhibited proliferation and promoted apoptosis via downregulating the methylglyoxal-glycolytic pathway. The study using the Glo1-silenced zebrafish model further supported the role of Glo1 in vascular development. This study underscores the pivotal role of Glo1 in peri-tumoral electroacupuncture, spotlighting a promising avenue for enhancing vascular normalization and improving TNBC treatment outcomes.

In many hematologic malignancies, the adoptive transfer of chimeric antigen receptor (CAR) T cells has demonstrated notable success; nevertheless, further improvements are necessary to optimize treatment efficacy. Current CAR-T therapies are particularly discouraging for solid tumor treatment. The immunosuppressive microenvironment of tumors affects CAR-T cells, limiting the treatment’s effectiveness and safety. Therefore, enhancing CAR-T cell infiltration capacity and resolving the immunosuppressive responses within the tumor microenvironment could boost the anti-tumor effect. Specific strategies include structurally altering CAR-T cells combined with targeted therapy, radiotherapy, or chemotherapy. Overall, monitoring the tumor microenvironment and the status of CAR-T cells is beneficial in further investigating the viability of such strategies and advancing CAR-T cell therapy.

Molecular targeted drugs and chimeric antigen receptor (CAR) T cell therapy represent specific biological treatments that have significantly improved the efficacy of treating hematologic malignancies. However, they face challenges such as drug resistance and recurrence after treatment. Combining molecular targeted drugs and CAR-T cells could regulate immunity, improve tumor microenvironment (TME), promote cell apoptosis, and enhance sensitivity to tumor cell killing. This approach might provide a dual coordinated attack on cancer cells, effectively eliminating minimal residual disease and overcoming therapy resistance. Moreover, molecular targeted drugs can directly or indirectly enhance the anti-tumor effect of CAR-T cells by inducing tumor target antigen expression, reversing CAR-T cell exhaustion, and reducing CAR-T cell associated toxic side effects. Therefore, combining molecular targeted drugs with CAR-T cells is a promising and novel tactic for treating hematologic malignancies. In this review article, we focus on analyzing the mechanism of therapy resistance and its reversal of CAR-T cell therapy resistance, as well as the synergistic mechanism, safety, and future challenges in CAR-T cell therapy in combination with molecular targeted drugs. We aim to explore the benefits of this combination therapy for patients with hematologic malignancies and provide a rationale for subsequent clinical studies.