Hierarchical Zeolitic Imidazolate Framework-8@Au Cluster Nanocarriers for In Situ Chimeric Antigen Receptor Macrophage Programming and Immunotherapy in Prostate Cancer.

Introduction: Our clinical program in chimeric antigen receptor T (CART) cell therapy has focused on targeting EGFR oncoproteins for glioblastoma (GBM). We have completed a phase I trial using CART cells directed to the EGFRvIII antigen and showed in situ uptake, proliferation, functional activation and antigen editing by CART cells in GBM tissue. This first clinical trial demonstrated two barriers to clinical efficacy. First, GBM heterogeneity was striking spatially and temporally, including the number of variants in EGFR. Second, CART cell therapy was associated with an adaptive anti-GBM response illustrated by an initial wave of CART activation followed by dramatic immunosuppression. These two features indicate that we need strategies to overcome GBM heterogeneity and the immunosuppressive tumor microenvironment (TME). Methods: We have used multiple CART variants, targeting both IL13Rα2 and EGFRvIII, in combination with selected immune checkpoint blockade inhibitors, to explore possible additive effects in both in vitro and in vivo GBM model systems on limiting the immunosuppressive GBM TME. Independently, we have developed a portfolio of CARTs with different binding specificities that target other homo- and heterodimers of EGFR oncoproteins, to address GBM heterogeneity. Results: Combination studies of CART cells with immune checkpoint blockade inhibitors revealed a non-homogenous response. Different CART structures and targets showed increased tumor killing activity with specific immune checkpoint blockade inhibition. Specifically, IL13Rα2-targeting CART cells had the best effect when paired with anti-CTLA4 treatment, while EGFRvIII-targeting CART cells had the largest effect when paired with anti-PD-1 treatment. In parallel to our combination therapy work, we have expanded our repertoire of CART constructs for targeting EGFR oncogenic alleles with extracellular domain mutations by utilizing antibody phage display technology. EGFR-targeting antibody sequences were incorporated into viral constructs and transduced into T cells. We have shown variable killing with these novel CART constructs in GSC/PDX models of GBM heterogeneity. Conclusion: Our initial experience with CART cells in GBM suggested that although a single intravenous infusion results in CART cell bioactivity in the brain, overcoming the adaptive changes in the local TME and addressing antigen heterogeneity may improve the clinical efficacy of CART-directed strategies. Our combination work showed that different CART constructs cooperate with immune checkpoint blockade inhibition differentially. This selective pairing suggests that a more personalized immunophenotypic assessment may result in higher efficacy therapeutic combinations. In addition, development of a broad portfolio of both selective and promiscuous CART constructs targeting EGFR in its various forms gives us the potential to cover a larger percentage of both the GBM tumor volume and regionally-specific tumor cells within a single GBM. Citation Format: Zev A. Binder, Yibo Yin, Radhika Thokala, Donald M. O'Rourke. Combinatorial platform for CART cell therapy for glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-340.

The efficacy of chimeric antigen receptor T (CAR-T) cells for solid tumors remains unsatisfactory due to the limited tumor infiltration and immunosuppressive microenvironment. To overcome these limitations, the genetically engineered recombinant oncolytic adenoviruses (OAVs) that conditionally replicate in tumor cells were developed to modify the tumor microenvironment (TME) to facilitate CAR-T-mediated tumor eradication. Here in the present study, a novel recombinant OAV carrying CCL5, IL12, and IFN-γ controlled by Ki67 promoter was constructed (named AdKi67-C3). The antitumor activity of AdKi67-C3 was tested in vitro and in vivo by using mono administration or combing with CAR-T cells targeting B7H3. It proved that CCL5 expressed by AdKi67-C3 indeed induced more CAR-T migration in vitro and CAR-T infiltration in tumor mass in vivo. Meanwhile, cytokines of IFN-γ and IL12 secreted by AdKi67-C3-infected tumor cells significantly promoted proliferation and persistence of CAR-T cells in vitro and in vivo. In tumor-bearing xenograft mouse models of kidney, prostate or pancreatic cancer, local pretreatment with AdKi67-C3 dramatically enhanced CAR-T cell efficacy and eliminated local and distant tumors. More importantly, mice achieving complete tumor regression resisted to re-challenge with the same tumor cells, suggesting establishment of long-term antitumor immune response. Therefore, OAVs armored with cytokines could be developed as a bioenhancer to defeat the immunosuppressive microenvironment and improve therapeutic efficacy of CAR-T in solid tumors.

Prostate cancer (PCa) is one of the most common malignancies in men, and metastatic castration-resistant PCa (mCRPC) has limited treatment options. While chimeric antigen receptor T (CAR-T) therapy has revolutionized treatment of hematologic cancers, its efficacy in PCa is constrained by factors such as scarce tumor-specific antigens, an immunosuppressive tumor microenvironment (TME), antigen heterogeneity, and safety issues (e.g., cytokine release syndrome). We performed a comprehensive literature review of CAR-T therapy in PCa. We summarized known PCa-specific CAR targets, identified major TME-related and technical barriers, and highlighted recent advances in CAR engineering (including armored CAR-T cells, gene editing, and metabolic reprogramming) as well as combination approaches with other therapies. Emerging strategies show promise for overcoming these obstacles. Next-generation CAR designs, such as cytokine-armed CAR-T cells, may enhance T cell infiltration and persistence despite the suppressive TME. Modulating tumor metabolism and immune checkpoints can reverse T cell exhaustion. Multi-antigen CARs and targeted gene edits (for example, PD-1 disruption) may limit antigen escape. Early clinical trials in PCa have demonstrated CAR-T cells specifically recognizing prostate-associated antigens and eliciting antitumor immune responses, although durable remissions remain rare. CAR-T therapy for prostate cancer is a rapidly advancing field. This review provides an updated perspective on CAR-T targets, engineering strategies, and combination approaches in PCa. Ongoing innovations in CAR design and therapeutic combinations offer the potential to develop more effective and durable CAR-T treatments for advanced prostate cancer.

Chimeric antigen receptor T (CAR-T) cell therapy achieves remarkable success in hematological cancers, but its efficacy is severely limited in solid tumors by formidable obstacles including physical barriers, the highly immunosuppressive tumor microenvironment (TME), and antigen escape. To address these persistent challenges, chimeric antigen receptor-macrophage (CAR-M) therapy emerges as a promising alternative, leveraging intrinsic advantages of macrophages like unparalleled tumor infiltration, powerful phagocytosis, and high plasticity. The evolution of CAR-M is primarily defined by the intracellular signaling domain. CAR-M exerts its anti-tumor effects through multifaceted mechanisms, including direct enhanced phagocytosis and tumor cell killing, TME remodeling by repolarizing to a pro-inflammatory M1-like phenotype, releasing anti-tumor effectors, and degrading the extracellular matrix (ECM), and the activation of adaptive immunity via efficient antigen presentation. Despite its promise, CAR-M faces hurdles such as TME physical barriers and the potential for M2-like re-education. Current optimization strategies focus on enhancing tumor infiltration, overcoming immunosuppression with "armored" CAR-Ms, and improving safety with suicide switches. Encouraging pre-clinical data accelerates CAR-M into early-phase clinical trials for solid tumors, and the platform's utility is also being explored beyond oncology in infectious, autoimmune, and neurodegenerative diseases.

Co-activating the intrinsic FcRγ/TLR4 signaling axis enhances the antitumor activity of NKG2D CAR-macrophages against prostate cancer.

BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors. Macrophages are abundant in the tumor microenvironment, making them an attractive target for therapeutic intervention. While current immunotherapies, including immune checkpoint inhibition (ICI) and chimeric antigen receptor T (CAR-T) cells, have shown limited efficacy in pancreatic cancer, a novel approach involving chimeric antigen receptor macrophages (CAR-M) has, although promising, not been explored in pancreatic cancer. In this study, we first investigated the role of CAR-M cells targeting c-MET in pancreatic cancer.MethodsThe effectiveness and rationality of c-MET as a target for CAR-M in pancreatic cancer were validated through bioinformatic analyses and immunohistochemical staining of samples from pancreatic cancer patients. We utilized flow cytometry and bioluminescence detection methods to demonstrate the specific binding and phagocytic killing effect of CAR-M on pancreatic cancer cells. Additionally, we observed the process of CAR-M engulfing pancreatic cancer cells using confocal microscopy and a long-term fluorescence live cell imaging system. In an in situ tumor model transplanted into NOD/SCID mice, we administered intraperitoneal injections of CAR-M to confirm its inhibitory function on pancreatic cancer. Furthermore, we validated these findings in human monocyte-derived macrophages (hMDM).ResultsBioinformatics and tumor tissue microarray analyses revealed significantly higher expression levels of c-MET in tumor tissues, compared to the paired peritumoral tissues, and higher c-MET expression correlated with worse patient survival. CAR-M cells were engineered using human monocytic THP-1 cell line and hMDM targeting c-MET (CAR-M-c-MET). The CAR-M-c-MET cells demonstrated highly specific binding to pancreatic cancer cells and exhibited more phagocytosis and killing abilities than the pro-inflammatory polarized control macrophages. In addition, CAR-M-c-MET cells synergized with various cytotoxic chemotherapeutic drugs. In a NOD/SCID murine model, intraperitoneally injected CAR-M-c-MET cells rapidly migrated to tumor tissue and substantially inhibited tumor growth, which did not lead to obvious side effects. Cytokine arrays and mRNA sequencing showed that CAR-M-c-MET produced higher levels of immune activators than control macrophages.ConclusionsThis study provides compelling evidence for the safety and efficacy of CAR-M therapy in treating pancreatic cancer. The results demonstrate that CAR-M-c-MET significantly suppresses pancreatic cancer progression and enhances the effectiveness of cytotoxic chemotherapy. Remarkably, no discernible side effects occur. Further clinical trials are warranted in human pancreatic cancer patients.

Acute myeloid leukaemia (AML) remains the most common type of leukaemia in adults. Despite advances in conventional therapies, high relapse rates persist, underscoring the need for novel approaches such as chimeric antigen receptor T (CAR‐T) cell therapy. C‐type lectin‐like molecule‐1 (CLL1)‐targeted CAR‐T emerges as a promising treatment for relapsed/refractory (R/R) AML. Although approximately 70% patients achieved remission, only a subset achieved minimal residual disease‐negative remission, which still has much room for improvement. The main reasons for the failure of CLL1 CAR‐T‐cell therapy include: (1) persistence of CLL1‐negative AML cells persist due to antigen escape; (2) downregulation of interleukin (IL)‐12 and other cytokines by the immunosuppressive tumour microenvironment (TME), contributing to the exhaustion of both endogenous T cells and CLL1 CAR‐T cells.We synthesise a combination of CAR‐engineered dendritic cells (CAR‐DCs) and CLL1 CAR‐T cells to overcome current limitations. CAR‐DCs enhance antigen cross‐presentation to activate endogenous T cells against antigen‐negative clones, secrete immunostimulatory cytokines (e.g., IL‐12) to sustain CAR‐T activity, and remodel the TME. Key challenges involve optimising CAR designs (e.g., incorporating Fms‐like tyrosine kinase 3 ligand [FLT‐3L] or CD40 signalling domains), mitigating toxicity and establishing clinical administration protocols.In this review, a focused discussion was provided on the specific challenges limiting CLL1‐targeted CAR‐T‐cell therapy in R/R AML, namely antigen escape and the TME, and a novel combination strategy of CAR‐DCs with CLL1 CAR‐T cells was proposed as a promising approach to mitigate these barriers. Here, the rationale, current research advances, and future perspectives of this synergistic strategy were critically examined.HighlightsOur earlier clinical trials showed that C‐type lectin‐like molecule‐1 (CLL1)‐targeted therapy for refractory/relapse acute myeloid leukaemia (AML) was validated, which still has a considerable room for improvement.We summarise the clinical trials and basic research on the dendritic cell (DC) therapy and chimeric antigen receptor‐engineered DC (CAR‐DC) therapy.We explored the synergistic mechanism and prospects of CLL1 CAR‐DC cells combined with CLL1 CAR‐T cells in AML.

IntroductionEffective infiltration of chimeric antigen receptor T (CAR-T) cells into solid tumors is critical for achieving a robust antitumor response and improving therapeutic outcomes. While CAR-T cell therapies have succeeded in hematologic malignancies, their efficacy in solid tumors remains limited due to poor tumor penetration and an immunosuppressive tumor microenvironment. This study aimed to evaluate the potential of low-dose radiotherapy (LDRT) administered before T-cell therapy to enhance the antitumor effect by promoting CAR-T cell infiltration. We hypothesized that combining LDRT with T-cell therapy would improve tumor control and survival compared to either treatment alone.MethodsWe investigated this hypothesis using two NSG mouse models bearing GSU or CAPAN-2 solid tumors. The mice were treated with engineered CAR-T cells targeting guanyl cyclase-C (GCC) or mesothelin as monotherapy or in combination with LDRT. Additionally, we extended this approach to a C57BL/6 mouse model implanted with MC38-gp100+ cells, followed by adoptive transfer of pmel+ T cells before and after LDRT. Tumor growth and survival outcomes were monitored in all models. Furthermore, we employed atomic force microscopy (AFM) in a small cohort to assess the effects of radiotherapy on tumor stiffness and plasticity, exploring the role of tumor nanomechanics as a potential biomarker for treatment efficacy.ResultsOur results demonstrated enhanced tumor control and prolonged survival in mice treated with LDRT followed by T-cell therapy across all models. The combination of LDRT with CAR-T or pmel+ T-cell therapy led to superior tumor suppression and survival compared to monotherapy, highlighting the synergistic impact of the combined approach. Additionally, AFM analysis revealed significant changes in tumor stiffness and plasticity in response to LDRT, suggesting that the nanomechanical properties of the tumor may be predictive of therapeutic response.DiscussionThe findings of this study highlight the transformative potential of incorporating LDRT as a precursor to adoptive T-cell therapy in solid tumors. By promoting CAR-T and pmel+ T-cell infiltration into the tumor microenvironment, LDRT enhanced tumor control and improved survival outcomes, offering a promising strategy to overcome the challenges associated with CAR-T therapy in solid tumors. Additionally, the changes in tumor nanomechanics observed through AFM suggest that tumor stiffness and plasticity could be biomarkers for predicting treatment outcomes. These results support further investigation into the clinical application of this combined approach to improve the efficacy of cell-based therapies in patients with solid tumors.

Chimeric antigen receptor T (CAR‐T) cell therapy, which targets CD19 for hematological malignancies, represents a breakthrough in cancer immunotherapy. However, some patients may develop resistance to CAR‐T treatment, underscoring the importance of optimizing CAR‐T design to enhance responsiveness. Here, we investigated the impact of different subpopulations in anti‐CD19 CAR‐T cells on the tumoricidal effect. Different populations of anti‐CD19 CAR‐T cells were isolated by magnetic‐activated cell sorting (MACS). Their lytic activities on the acute lymphocytic leukemia cell line SUP‐B15 and diffuse large B‐cell lymphoma EB‐3 cell line were examined in a co‐culture system. The anti‐tumorigenic outcome of different CAR‐T cell compositions was evaluated in a xenograft mouse model of EB‐3 cells. CD8+CAR‐T cells exhibited the most potent tumoricidal activity against SUP‐B15 and EB‐3 cells. Additionally, CD4+ T helper cells enhanced the lytic effects of CD8+ CAR‐T cells by increasing the availability of interleukin‐2 (IL‐2). Depleting CD25+Treg (T regulatory) cells from CD4+CAR‐T population further augmented the tumoricidal activity of CD8+CAR‐T cells by preventing IL‐2 deprivation. Consistently, in vivo experiments demonstrated that the CD4+CD25+ Treg population dampened the antitumor activity of CD8+CAR‐T cells, while depletion of Tregs from CD4+CAR‐T cells enhanced the tumoricidal effect. These findings emphasize the potential role of CAR Treg cells in therapeutic resistance, suggesting that the depletion of Tregs in the anti‐CD19 CAR‐T population may serve as a strategy to augment the anticancer effect of CD8+CAR‐T cells.

BackgroundDespite the remarkable efficacy achieved by CAR-T therapy in hematologic malignancies, application in solid tumors has been challenging. We previously developed human CAR-M and demonstrated that adoptive transfer of CAR-M...

Chimeric antigen receptor T (CAR-T) cell therapy has shown remarkable success in hematologic malignancies but has encountered challenges in effectively treating solid tumors. One major obstacle is the presence of the immunosuppressive tumor microenvironment (TME), which is mainly built by myeloid-derived suppressor cells (MDSCs). Recent studies have shown that MDSCs have a detrimental effect on CAR-T cells due to their potent immunosuppressive capabilities. Targeting MDSCs has shown promising results to enhance CAR-T immunotherapy in preclinical solid tumor models. In this review, we first highlight that MDSCs increase tumor proliferation, transition, angiogenesis and encourage circulating tumor cells (CTCs) extravasation leading to tumor progression and metastasis. Moreover, we describe the main characteristics of the immunosuppressive activities of MDSCs on T cells in TME. Most importantly, we summarize targeting therapeutic strategies of MDSCs in CAR-T therapies against solid tumors. These strategies include (1) therapeutic targeting of MDSCs through small molecule inhibitors and large molecule antibodies; (2) CAR-T targeting cancer cell antigen combination with MDSC modulatory agents; (3) cytokine receptor antigen-targeted CAR-T indirectly or directly targeting MDSCs reshapes TME; (4) modified natural killer (NK) cells expressing activating receptor directly targeting MDSCs; and (5) CAR-T directly targeting MDSC selective antigens. In the near future, we are expected to witness the improvement of CAR-T cell therapies for solid tumors by targeting MDSCs in clinical practice.

Editorial on the Research Topic Chimeric antigen receptor T (CAR-T) cells have shown promising efficacy in treating hematological malignancies, particularly CD19 CAR-T for B-cell acute lymphoblastic leukemia with a 70~94% complete remission rate (1). However, antigen escape presents a significant challenge for the long-term effectiveness of CAR-T (1-3), and using CAR-T to treat solid tumors faces obstacles due to the lack of safe and effective treatment targets (1). Therefore, finding new targets for CAR-T therapy is critical. The ideal target of CAR-T therapy should be specifically expressed or remarkably upregulated on the surface of tumor cells. In addition to this classic target screening method, there are also some new screening methods that deserve attention. For example, peptidecentric CARs have the potential to vastly expand the pool of immunotherapeutic targets to include non-immunogenic intracellular oncoproteins (4). In addition to screening new targets on tumor cells, we can also focus on targets on CAR-T cells, such as canonical BRG1/BRM-associated factor (5) and PD1 (6). The strategy of obtaining potential targets for immunotherapy through high-throughput data analysis (Chen et al.) has crucial implications for screening new targets for CAR-T therapy. The use of multidimensional omics data advanced CAR-T cell therapy (7). DNA sequencing have identified numerous tumor-associated somatic mutations, some of which might generate tumor-specific neoantigens and could potentially serve as novel targets for CAR-T therapy (8, 9). Genome-wide pooled CRISPR-Cas9 knockout library screening has resulted in the identification of key genes involved in T cell cytotoxicity (10) and genetic alterations in tumor cells that influence resistance to treatment (11). Epigenetic reprogramming of CAR-T cells also has the potential to enhance T cell cytotoxicity (12). Meanwhile, integrating proteomics and transcriptomics is also a reliable strategy for screening CAR-T therapeutic targets (13). Several new targets for CAR-T therapy in hematological malignancies have been reported. GPRC5D has been identified as a potential target for CAR-T treatment of multiple myeloma in preclinical research by Smith et al. (14) and confirmed by subsequent clinical trials (15-17). In this Research Topic, Wu et al. suggested in a preclinical study that Frontiers in Immunology frontiersin.org 01

The treatment of some patients with hematological malignancies has been transformed by chimeric antigen receptor T (CAR-T) cells. However, a large clinical need remains for more effective CAR-T therapies and to expand their use to broader patient groups including those with solid tumors. The exogenous administration of IL-2 and IL-21 were shown to enhance the engraftment, persistence, and functionality of CAR-Ts in preclinical models. However, clinical use of such cytokines is limited due to their pleiotropic nature that can result in toxicity and undesired effects on endogenous immune cells. To overcome this, we applied our cis-targeting technology to develop CAR-T specific IL-2 and IL-21 molecules that selectively activate CAR-Ts and exhibit minimal activity on non-CAR cells. Cis-targeted IL-2 and IL-21 molecules are comprised of a targeting antibody fused to an affinity-attenuated cytokine mutein, the activity of which is rescued due to the avidity provided by the targeting arm. This enables the highly selective delivery of cytokine support to human CAR-T cells. We engineered two types of fusions targeting either 1) the CAR directly without blocking CAR antigen recognition (CAR-IL2) or 2) an exogenous cell surface tag (non-signaling truncated epidermal growth factor receptor [EGFRt]) co-expressed with the CAR (EGFRt-IL2 and EGFRt-IL21). We characterized these molecules in vitro and in vivo. Both CAR- and EGFRt-targeted molecules demonstrated >100-fold preferential STAT activation of CAR-T cells over non-CAR cells. Unexpectedly, CAR-targeted fusions induced substantial antigen independent cytokine release, whereas fusions targeting the EGFRt tag did not. We found that antigen independent cytokine release was more suppressed by a LCK inhibitor rather than a JAK inhibitor, suggesting that downstream CAR signaling was the major contributor, compared to cytokine receptor signaling. In vivo studies examined the anti-tumor activity of the tag-targeted cytokine fusions given their desired safety profile. A single dose of either EGFRt-IL2 or EGFRt-IL21 on day 1 or day 7 following a sub-optimal infusion of CD19 CAR-T cells (0.1 x106) induced strong tumor regression and relapse free survival for >70 days in an aggressive NALM-6 leukemia model. EGFRt-IL21 induced a sustained 10-fold expansion of CAR-T numbers over PBS in the blood by day 7. In contrast, EGFRt-IL2 induced a delayed but greater expansion (1000-fold over PBS) by day 14 suggestive of a mechanistic difference of the two cis-targeted molecules. Analysis of EGFRt-IL2 and EGFRt-IL21 in a solid tumor model using CAR-T cells targeting endogenous tumor antigen showed similar anti-tumor effects. Cis-targeted IL-2 and IL-21 fusion molecules directed by anti-tag EGFRt antibodies confer selective enhancement of CAR-T cells with a minimal safety risk, representing a promising approach as an adjuvant CAR-T therapy. Citation Format: Nathan D. Mathewson, Wei Chen, Paul Bessette, Sara Sleiman, Meghana Sukthankar, Kelly D. Moynihan, Chris Kimberlin, Terrence Park, Audrey Hollingsworth, Saar Gill, Andy Yeung, Ivana Djuretic. Engineered cell surface tag-targeted IL-2 and IL-21 selectively and safely enhance CAR-T anti-tumor activity via different mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1847.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies, characterized by late diagnosis, early metastasis, and resistance to conventional therapies. A major barrier to effective treatment is its desmoplastic and immunosuppressive tumor microenvironment, which restricts T-cell infiltration and dampens responses to immune checkpoint inhibitors (ICI). These features highlight the urgent need for innovative immunotherapeutic strategies capable of overcoming PDAC's immunologic and physical barriers. Chimeric antigen receptor (CAR)-macrophage (CAR-M) therapy has emerged as a promising approach to address these challenges. Unlike CAR-T or CAR-NK cells, CAR-Ms can efficiently infiltrate tumors, remodel the tumor microenvironment, phagocytose tumor cells, and stimulate adaptive immunity. This review highlights recent advances in CAR-M therapy for solid tumors, with an emphasis on PDAC. Preclinical studies show that CAR-Ms enhance antigen presentation, secrete proinflammatory cytokines, and recruit cytotoxic T cells, thereby amplifying antitumor responses. Progress in CAR-M engineering-such as dual-targeting strategies, CRISPR-based modifications, and combinations with ICIs or other therapies-further strengthens their therapeutic potential. Importantly, early-phase clinical trials in solid tumors support the safety, tolerability, and tumor-modulating capacity of CAR-Ms, laying the groundwork for their application in PDAC. To fully harness CAR-M therapy in PDAC, several challenges must be addressed, including improving CAR-M persistence and efficacy, optimizing tumor-specific targeting, developing scalable and cost-effective manufacturing platforms, and integrating strategic combinations with other therapies, such as ICIs and KRAS inhibitors. With continued innovation and clinical validation, CAR-M therapy has the potential to transform PDAC treatment, fulfill critical unmet clinical needs, and provide new hope for patients.

Breaking the immunosuppressive barrier: an armored CAR-M biotechnology with the original M1 phenotype dominance rescues antitumor immunity.