CAR-T cell therapy in china: innovations, challenges, and strategic pathways

Abstract

Cancer immunotherapy has transformed oncology, with CAR-T cell therapy emerging as a cornerstone of personalized treatment for hematologic malignancies. In China, rapid advancements in domestically developed CAR-T therapies have achieved clinical outcomes comparable to global benchmarks, with overall response rates (ORR) of 79–89% in B-cell malignancies and 64% 12-month progression-free survival in multiple myeloma. Despite these successes, CAR-T application in solid tumors remains hindered by antigen heterogeneity, immunosuppressive microenvironments, and on-target/off-tumor toxicity. To address these barriers, China has pioneered innovative strategies, including dual-target CAR-T constructs, armored CAR-Ts secreting immunomodulatory cytokines, and synergistic integration with traditional Chinese medicine, which enhances CAR-T efficacy by inhibiting myeloid-derived suppressor cells and reducing cytokine release syndrome. Notably, preclinical studies demonstrate that Huangqin increases tumor regression rates from 40 to 65% in lung cancer models when combined with CAR-T therapy. Concurrently, China is reshaping accessibility through policy innovations such as the “1 + 3 + N” multi-tiered payment system and regional insurance pilots, which reduce patient costs by 50%. Strategic investments in automated manufacturing and global regulatory harmonization further position China as a leader in cost-effective CAR-T development. However, challenges persist in solid tumor targeting, international market integration, and long-term safety monitoring. Future directions emphasize precision engineering, AI-driven treatment optimization, and cross-border collaborations to advance next-generation therapies. By balancing innovation, affordability, and policy agility, China is poised to drive the global evolution of cancer immunotherapy while addressing unmet needs in both hematologic and solid malignancies.

Introduction

Cancer immunotherapy has revolutionized oncology by reprogramming the immune system to target malignancies, with chimeric antigen receptor T-cell (CAR-T) therapy emerging as a transformative approach for hematologic cancers. While immune checkpoint inhibitors (ICIs) and bispecific antibodies (BsAbs) have expanded therapeutic options, CAR-T therapy stands at the forefront of personalized immunotherapy due to its ability to engineer patient-derived T cells for precise tumor targeting and eradication [1–3]. Since the 2017 FDA approval of CD19-targeted CAR-T therapies, this approach has achieved unprecedented success in relapsed/refractory B-cell malignancies, with complete remission rates exceeding 50% in global trials [4, 5]. In China, the development of CAR-T therapy has accelerated rapidly, with four domestically developed products, such as Arelcabtagene autoleucel and Equecabtagene autoleucel, approved for lymphoma and myeloma since 2021. These therapies have demonstrated comparable efficacy to their Western counterparts while addressing unique regional challenges, including cost and manufacturing scalability [6, 7]. Despite these advances, CAR-T therapy faces limitations in treating solid tumors due to antigen heterogeneity and immunosuppressive tumor microenvironments—challenges that are also shared, to varying degrees, by ICIs and BsAbs [8, 9]. ICIs, exemplified by PD-1/PD-L1 inhibitors, have shown durable responses in select solid tumors but are hindered by primary resistance [10]. Similarly, BsAbs, such as Emicizumab and Epcoritamab, bridge immune and tumor cells but are limited by cytokine release syndrome (CRS) and antigen diversity [11, 12]. In contrast, CAR-T research in China has prioritized overcoming these barriers through innovative strategies such as dual-target CAR-Ts (e.g., CD19/BCMA), armored CAR-Ts that secrete immunostimulatory cytokines, and integration with traditional Chinese medicine to modulate the tumor microenvironment [13–16]. This review focuses on CAR-T therapy as the central pillar of China’s advancements in immunotherapy, contextualizing its progress relative to global benchmarks. It also briefly discusses the complementary roles of ICIs and BsAbs. By analyzing clinical outcomes, regulatory frameworks, and cost-optimization strategies unique to China, we aim to highlight the growing influence of Chinese research in shaping the future of cancer immunotherapy.

CAR-T therapy: hematologic vs. solid tumors

Success in hematologic malignancies

CAR-T cell therapy has emerged as a groundbreaking advancement in the treatment of hematologic cancers, leveraging the ability of engineered T cells to specifically target tumor antigens such as CD19 and BCMA[17, 18]. The clinical success of CAR-T therapies, including Arelcabtagene autoleucel and Equecabtagene autoleucel in China, underscores the transformative potential of personalized immunotherapy in cancer treatment. These therapies have demonstrated remarkable clinical outcomes, with ORR of 79–89% for CD19-targeted CAR-T in B-ALL from Chinese Phase II single-arm trials (e.g., Arelcabtagene autoleucel, NCT03563810) [21–23] and 89.6% ORR for BCMA CAR-T (Equecabtagene autoleucel) in multiple myeloma from the FUMANBA-1 trial (NCT03784192), a single-arm nonrandomized study [20]. The 64% 12-month PFS in multiple myeloma surpasses historical chemotherapy outcomes and is derived from the same Chinese trial [20]. Recently, there has been growing interest in the potential synergy between CAR-T therapy and traditional Chinese medicine (TCM), particularly Huangqin (Scutellaria baicalensis), in modulating the tumor microenvironment and enhancing treatment efficacy. As noted, active components of Huangqin, such as baicalin and baicalein, have shown significant promise in reducing the immunosuppressive effects within the tumor microenvironment. This is primarily attributed to their ability to inhibit myeloid-derived suppressor cells (MDSCs) and reduce the levels of suppressive cytokines, such as IL-10 and TGF-β, which typically attenuate immune responses [24–27]. Additionally, Huangqin promotes the upregulation of pro-inflammatory cytokines such as interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α), which enhance T cell activation and prevent T cell exhaustion, a critical challenge in optimizing CAR-T therapy efficacy [28].

Preclinical studies suggest a potential synergistic effect between Huangqin (Scutellaria baicalensis) components (e.g., baicalin/baicalein) and CAR-T therapy in human non-small cell lung cancer xenograft models established with NCI-H1975 cells in immunocompromised NSG mice. Baicalein modulates the immune microenvironment by inhibiting MDSCs, with single-agent baicalin/baicalein showing 30%−60% tumor inhibition rates [29–31] and CAR-T monotherapy achieving 20%−60% response rates in preclinical settings [32, 33]. Specifically, in a murine xenograft model of lung cancer (n = 12 per group) treated with the combination of Huangqin extract (200 mg/kg, intragastric administration, daily for 21 days) and CD133-targeted CAR-T cells (1 × 10^6 cells/mouse, intravenous injection on day 7), the tumor regression rate was significantly increased from 40% (CAR-T monotherapy group) to 65% (combination group) (p < 0.01, χ² test). This significant improvement in tumor regression indicates a robust synergistic effect between Huangqin and CAR-T therapy in this preclinical model. These results, together with preliminary clinical data showing improved overall response rates and reduced severity of cytokine release syndrome (CRS) when Huangqin is combined with CAR-T, suggest that TCM may offer an innovative approach to improving CAR-T therapy outcomes, particularly in solid tumors [34, 35]. The integration of such therapies could not only improve the efficacy of CAR-T in solid tumors but also enhance its potential in hematologic malignancies, offering a multifaceted approach to treat diverse patient populations [22, 36]. The combination of CAR-T therapy with TCM represents an exciting frontier in cancer immunotherapy, exemplifying the broader trend of integrating modern medical technologies with traditional approaches to address the complex challenges of cancer treatment. Emerging evidence suggests that this integrated strategy could lead to more durable and comprehensive responses, both in hematologic and solid tumors. Besides, Quantitative Comparison Table of Chinese vs. US CAR-T Efficacy is in Table 1.1

Table 1.

Quantitative comparison table of Chinese vs. US CAR-T efficacy

Malignancy	Chinese CAR-T therapy	Efficacy data	US CAR-T therapy	Efficacy data	References
DLBCL	Arelcabtagene autoleucel	ORR 79–89%	Yescarta	ORR 72%	[6, 21]
Multiple myeloma	Equecabtagene autoleucel	ORR 89.6%, 12-mo PFS 64%	Abecma	ORR 72%, 12-mo PFS 58%	[20, 23]
B-ALL	CD19-targeted CAR-T	ORR 79–89%	Tisagenlecleucel	ORR 81%	[19, 22]

Challenges in solid tumors

The application of CAR-T therapy to solid tumors is hindered by three interconnected challenges related to tumor biology and the complexity of the tumor microenvironment (TME). First, antigen heterogeneity presents a significant obstacle, as solid tumors do not exhibit the uniform expression of lineage-specific antigens seen in hematologic malignancies. For example, glypican-3 (GPC3), a frequently targeted antigen in Chinese clinical trials for hepatocellular carcinoma (HCC), is expressed in only 40–60% of HCC patients in China, resulting in incomplete tumor cell eradication and eventual relapse [37]. Similarly, Claudin18.2, a promising gastric cancer target in China, demonstrates variable expression across different tumor subtypes, complicating patient selection [38]. Second, the immunosuppressive TME in solid tumors severely impairs CAR-T cell efficacy. Elevated levels of TGF-β and IL-10 in solid tumors from Chinese patients have been shown to suppress CAR-T cell proliferation and cytotoxicity by upregulating exhaustion markers such as TIM-3 and LAG-3 [39]. A study further revealed that gastric cancer stromal cells reduced CAR-T cytotoxicity by 70% through dual PD-L1 and indoleamine 2,3-dioxygenase (IDO)-mediated immunosuppression, underscoring the critical role of the TME in resistance to therapy [40]. Third, on-target/off-tumor toxicity remains a major safety concern. Targeting antigens like Claudin18.2, which is expressed in 60% of Chinese gastric cancers as well as in normal gastric mucosa, has led to severe adverse effects [41]. In a Phase I, single-center, open-label trial (N = 36) of Claudin18.2-targeted CAR-T therapy (CT041) in advanced gastric cancer, 28% (10/36) of patients developed grade ≥ 3 gastritis due to off-tumor toxicity toward healthy gastric mucosa [42]. This highlights the delicate balance between efficacy and safety in solid tumor CAR-T applications, where antigen expression on normal tissues remains a critical challenge. These challenges collectively underscore the need for innovative strategies to enhance antigen specificity, modulate the TME, and mitigate off-tumor effects in CAR-T therapies for solid tumors.

China’s strategic innovations and future directions

Novel targets and cost optimization

China is at the forefront of developing innovative solutions to address the challenges associated with CAR-T therapy in solid tumors. These strategies include novel target development, combination therapies, and cost-reduction initiatives [43]. Target innovation has become a key feature of CAR-T research in China. Approximately 43% of Chinese clinical trials for solid tumors focus on glypican-3 (GPC3) in hepatocellular carcinoma (HCC) and Claudin18.2 (CLDN18.2) in gastric cancer, compared to just 22% of global trials targeting HER2/PSMA. For instance, the NCT04503980 trial of CLDN18.2-targeted CAR-T (CT041) in advanced gastric cancer achieved an objective response rate (ORR) of 48.6%, which is notably higher than the 32% ORR reported in HER2-targeted CAR-T trials in the United States [42]. Remarkably, CT041 demonstrated a disease control rate (DCR) of 75.5% in gastrointestinal tumors, with complete tumor regression observed in some heavily pretreated patients, including those with pancreatic cancer [42]. Another emerging approach involves the combination of CAR-T with traditional Chinese medicine (TCM). The compound Huangqin (Scutellaria baicalensis) has been shown to enhance CAR-T persistence by inhibiting myeloid-derived suppressor cells (MDSCs) in preclinical lung cancer models [24, 44]. This strategy leverages TCM’s immunomodulatory properties to counteract the immunosuppressive tumor microenvironment (TME), which is a significant barrier in solid tumors. Additionally, cost-reduction strategies through streamlined manufacturing and policy innovation are reshaping the accessibility of CAR-T therapies [45]. Despite four unsuccessful attempts to list CAR-T in China’s National Reimbursement Drug List (NRDL) due to pricing disputes, a multi-tiered payment system (“1 + 3 + N”)—combining basic insurance, commercial insurance, and patient co-payment—is being explored to improve affordability [46]. These efforts aim to strike a balance between sustainable innovation and patient access, positioning China as a leading global player in cost-effective CAR-T development. Figure 1 showed the technological innovation directions of China’s CAR-T therapy

Fig. 1.

Technological innovation directions of China's CAR-T therapy

Policy synergy and global collaboration

In recent years, the rapid development of CAR-T therapy in China has prompted the government to explore pilot programs and multi-tiered payment models to alleviate the financial burden on patients [46]. One notable initiative is the “Hu Hui Bao” program, launched in 2023 in Shanghai. This program offers up to 50% reimbursement for eligible CAR-T treatments, significantly reducing out-of-pocket expenses for patients. For instance, a patient undergoing CAR-T therapy with Yescarta^® (priced at 1.2 million RMB) could receive a 500,000 RMB payout from Hu Hui Bao, reducing their out-of-pocket drug cost by 41.7% (from 1.2 million to 700,000 RMB) [47]. As of March 2024, the program has reimbursed over 33 million RMB for CAR-T treatments, benefiting nearly 60 patients in Shanghai [48]. Notably, this coverage applies solely to CAR-T drug costs and does not include hospitalization, nursing, or other treatment-related expenses. Actual out-of-pocket costs may still exceed 60% of total treatment fees, depending on additional medical needs [48]. Initial reports indicate that the program is available at key medical institutions in both urban and suburban areas of Shanghai. During its implementation, the program has adhered to principles of fairness, ensuring that all eligible patients have access. Moreover, it has emphasized the collection of real-time data and performance evaluations. Early feedback suggests that “Hu Hui Bao” has substantially reduced patient costs, enhanced treatment coverage, and increased patient satisfaction. Despite these promising results in Shanghai, the program has not yet been expanded nationwide. To further internationalize CAR-T therapy, China is actively seeking collaboration with global markets by attracting international investment, enhancing cross-border regulatory coordination, and adopting international standards [49]. These efforts aim not only to reduce treatment costs but also to create favorable conditions for Chinese CAR-T products to enter the global market, thereby establishing a complementary and mutually beneficial development model both domestically and internationally [50].

Future technological pathways

Looking ahead, the field of cancer immunotherapy is poised for significant breakthroughs in precision medicine, cell engineering, and combination therapies. Advanced techniques such as single-cell sequencing and spatial transcriptomics are expected to refine patient stratification, as demonstrated by emerging trials identifying predictive biomarkers for CAR-T efficacy in solid tumors [51]. Additionally, “armored” CAR-T cells, engineered to secrete IL-12 or resist TGF-β signaling, are showing promising results in early-phase clinical trials, improving persistence and efficacy within immunosuppressive microenvironments [52]. In the field of bispecific antibodies (BsAbs), research is expanding beyond dual immune checkpoint blockade to incorporate novel antigen pairs, addressing both tumor heterogeneity and immune suppression [53]. Furthermore, the rapid evolution of artificial intelligence (AI) and machine learning is transforming telemedicine platforms, enabling real-time monitoring and dynamic adjustment of immunotherapy regimens based on predictive analytics [54]. Meanwhile, immune checkpoint inhibitors (ICIs) continue to advance, with next-generation targets such as LAG-3 and TIM-3 aimed at overcoming resistance and expanding their applicability to a broader range of solid tumors [55]. Despite these advances, challenges such as tumor heterogeneity, resistance, and immune-related adverse events (irAEs) remain substantial obstacles [56]. Future strategies will focus on multi-omics integration and personalized treatment protocols, leveraging predictive biomarkers to enhance efficacy while minimizing toxicity. These efforts are expected to propel cancer immunotherapy toward greater maturity and broader global adoption.

Strategies for china’s CAR-T therapies

Table 2 compares the CAR-T development strategies, highlighting key differences between China and Western countries. In Western countries, CAR-T development predominantly focuses on specific cancer types and highly personalized treatment protocols, relying on well-established technological platforms [57]. In contrast, China places a strong emphasis on cost-effectiveness in CAR-T research, while accelerating clinical trial progress, supported by robust policy backing and advantageous market access [58]. Additionally, Western countries tend to impose more stringent drug regulations and data accumulation standards, whereas China benefits from more flexible approval processes and faster market promotion [59, 60]. Based on the comparative analysis in Table 1, this paper suggests three key strategies for China to enhance the accessibility and international competitiveness of its CAR-T therapies by drawing from the experiences of Western countries. First, China could expand insurance pilot programs, inspired by the Shanghai “Hu Hui Bao” initiative, which provided 50% reimbursement for CAR-T treatments in 2023. Extending similar pilot programs to high-demand regions such as Beijing and Guangdong, along with adopting an outcome-based payment model, could link reimbursement rates to CAR-T efficacy, thus alleviating financial pressures on national insurance funds. Second, China could accelerate conditional approvals by implementing real-world data (RWE) requirements, following the FDA’s Regenerative Medicine Advanced Therapy (RMAT) and Breakthrough Therapy (BPR) pathways. This approach would broaden the scope of conditional approvals and ensure long-term safety and efficacy monitoring while expediting CAR-T market entry. Finally, China should promote automated CAR-T manufacturing for scaled production. Western CAR-T manufacturers, such as Novartis, have implemented fully automated cell processing systems (e.g., the Prodigy system) to reduce costs and shorten production cycles. China should invest in similar automation technologies and optimize local supply chains to further reduce CAR-T treatment costs and enhance affordability.

Table 2.

CAR-T development strategy comparison: China vs. Western countries

Dimension	China	Western countries
Key Targets	CD19, BCMA, GPC3, Claudin18.2	CD19, BCMA, HER2, PSMA
Cost (Per Treatment)	$150,000	$400,000
Regulatory Pathway	Conditional approval + real-world evidence	FDA accelerated approval (RMAT/BPR)
Payment Model	1 + 3 + N multi-tier system	Outcome-based payment + commercial insurance
Manufacturing Process	Localized supply chain, optimized automation	Bioreactors like Novartis Prodigy system
Insurance Coverage	Regional pilots (e.g., Shanghai “Hu Hui Bao” covers 50%)	Primarily covered by private insurance, some government programs
Indication Expansion	Focused on solid tumors (e.g., GPC3 for HCC, Claudin18.2 for gastric cancer)	Mainly hematologic malignancies, limited solid tumor trials (HER2, PSMA)
Clinical Trials	Real-world evidence included in regulatory approval, shorter trial cycles	Large-scale RCTs, longer approval cycles

Conclusion

In conclusion, tumor immunotherapy has fundamentally transformed cancer treatment worldwide, with CAR-T cell therapy emerging as a cornerstone, particularly for hematologic malignancies. China’s rapid advancements in domestically developed CAR-T therapies have positioned it as a front-runner in the global landscape, marked by three key quantified milestones: clinical efficacy with overall response rates (ORRs) of 79–89% in B-cell malignancies and 64% 12-month progression-free survival (PFS) in multiple myeloma, comparable to international benchmarks; cost reduction through regional insurance pilots like “Hu Hui Bao,” which slashed patient out-of-pocket expenses by 41.7% and reimbursed over 33 million RMB for CAR-T treatments as of March 2024; and enhanced patient accessibility, with the multi-tiered payment system extending coverage to over 60 patients in Shanghai while ensuring equity across urban and suburban medical institutions. Despite these achievements, challenges remain in internationalizing CAR-T products, including gaining global regulatory recognition, harmonizing production standards, and addressing market competition. Future strategies should focus on optimizing policies, advancing automated manufacturing, fostering cross-border collaborations, and integrating innovations like traditional Chinese medicine—efforts essential for ensuring Chinese CAR-T therapies continue to benefit domestic patients and achieve broader global adoption.

Author contributions

LY, BD, PS, TW, TW，SJ and YW wrote the main manuscript text. All authors reviewed the manuscript.

Funding

This work was supported by the National Natural Science Cultivation Foundation of China of Liaoning Cancer Hospital (2021-ZLLH-18); The Natural Science Foundation of Liaoning (2024-MS-266); Shenzhen High-level Hospital Construction Fund; The Shenzhen Science and Technology Program (SGDX20201103095614039).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics, consent to participate, and consent to publish 

Not applicable.

Competing interests

The authors declare no competing interests.

Clinical trial number

Not applicable.