Description | SYPHU-CHINA

I. Epidemiological characteristics of liver cancer globally

1. Incidence rate and mortality rate

Global data: By 2025, the number of new cases of hepatocellular carcinoma is projected to surpass 1 million globally, with approximately 760,000 deaths, ranking third among cancer-related deaths. If no intervention is taken, the number of new cases will reach 1.52 million globally by 2050, with 1.37 million deaths (Lancet report, 2025).

Regional distribution: High-incidence areas: East Asia (China, Japan, South Korea), West Africa, Southeast Asia, with China accounting for 42.4% of global cases.

Low-incidence areas: Northern Europe, Australia, but alcoholic liver cancer is on the rise in Eastern Europe.

Data from China: In 2022, there were 367,700 new cases, with the mortality rate ranking second and the incidence rate approximately 30.3 per 100,000 individuals. The southeast coastal areas (such as Jiangsu, Fujian, and Guangdong) are high-incidence areas ("2022 Global Cancer Statistics Report").

2. Risk factors — Main causes

Viral hepatitis: HBV (39% in China), HCV (29.1% globally). Through universal screening, Italy has achieved a cure rate of over 95% for hepatitis C.

Metabolic liver disease: Obesity-associated liver cancer (MASLD) accounts for 8% of the global incidence rate, and is expected to increase to 11% by 2050. The incidence rate of "fatty liver cancer" among young people in China has surged by 25 times.

Alcohol and environmental factors: Alcoholic liver cancer is increasing fastest in Eastern Europe, with aflatoxin (such as in Qidong City) and drinking water pollution (such as cyanobacterial toxins) being regional risk factors.

3. Characteristics of the affected population

Age and gender: The incidence rate of males is 2-4 times higher than that of females. The median age of onset is 45 years in China, and over 60 years in Europe and America.

High-risk groups: Patients with chronic liver disease (hepatitis B/hepatitis C, cirrhosis); individuals with long-term alcohol abuse, obesity/diabetes; those with a family history of liver cancer or exposure to aflatoxin or chemical carcinogens.

Figure 1: Complications of liver cancer

II. Current situation of liver cancer in China

1. Incidence rate and epidemic trend

Data: The incidence rate in 2025 was 15.03 per 100,000, ranking fourth among malignant tumors, with a male mortality rate exceeding 40 per 100,000 (Shanghai and Fujian are high-incidence areas).

Regional differences: The mortality rate of male liver cancer in Qidong City, located on the southeast coast, has decreased by 51% through intervention (from 1972 to 2021), compared to the inland areas.

2. Risk factors

Dominant factor: HBV infection (accounting for 80% of the correlation), but vaccination has reduced the infection rate in children by 97%; aflatoxin (contamination of corn), water contamination (cyanobacterial toxins), and selenium deficiency; metabolic liver diseases (such as fatty liver) have become new threats, with obesity-related liver cancer cases increasing by 35% annually.

3. Current treatment status and progress

Surgery and interventional therapy: The 5-year survival rate after surgery at Zhongshan Hospital affiliated to Fudan University reached 70.7% (data from 2011 to 2020), with an improvement in early diagnosis rate (tumor diameter reduced from 10cm to 4cm); RAK cell therapy (pioneered internationally) has achieved a 1-year recurrence-free survival rate of 79% for high-risk patients (International Journal of Surgery, 2025).

Targeted therapy and immunotherapy: Lenvatinib and atezolizumab combined with bevacizumab have become first-line treatment options; CAR-T therapy has shown efficacy in advanced liver cancer, but its accessibility is still limited.

Prevention and screening: Hepatitis B vaccination has covered 95% of newborns. Qidong City has reduced the risk of liver cancer by 8 times through adjusting the staple food structure (from corn to rice). AFP+B-ultrasound screening has covered high-risk groups, and the early diagnosis rate has increased to 30.8% (in 2020).

III. International treatment progress and challenges

1. Prevention and control strategies

Vaccination: Japan has achieved a 5-year survival rate of 58% for liver cancer through universal hepatitis screening (with a coverage rate of 80%).

Hepatitis C treatment: Egypt achieves a cure rate of over 90% through domestically produced DAA drugs, while Italy establishes a national screening system.

Management of metabolic liver disease: WHO recommends "sugar tax" and alcohol warning labels to reduce the risk of obesity- and alcohol-related liver cancer.

2. Innovative therapies

Cell therapy: The autologous RAK cell injection (developed in China) has entered Phase II clinical trials, significantly reducing the risk of recurrence.

Non-invasive detection: The GALAD model (sensitivity 84-96%) and miRNA kit (AUC 0.941) are used for early diagnosis.

3. Regional differences and challenges

Resource allocation: Due to the high prevalence of HBV and the lack of screening in low-income countries (such as in Africa), the mortality rate of liver cancer is three times higher than that in developed countries.

Treatment accessibility: Targeted drugs are expensive in low-income countries, and only 30% of patients globally receive standardized treatment.

Data sources: Report of the Liver Cancer Commission of The Lancet in 2025, National Cancer Center of China, WHO official website, clinical data from Zhongshan Hospital affiliated to Fudan University.

IV. Application expansion of all-trans-retinoic acid in cancer treatment and feasibility analysis of its application in liver cancer treatment

1. Exploration of the application of all-trans-retinoic acid (ATRA) in the treatment of various cancers

All-trans retinoic acid (ATRA), as an active metabolite of vitamin A, was pioneered by the team of Chinese scientist Wang Zhenyi in the 1980s for the treatment of acute promyelocytic leukemia (APL). This pioneering approach made APL the first leukemia type treatable through induction differentiation, elevating the five-year survival rate of patients from less than 20% to over 90%, creating a miracle in the history of cancer treatment. ATRA achieves the effect of inducing tumor cell differentiation by directly binding to the active site of Pin1, a isomerase and a common key regulatory factor in carcinogenic signaling pathways in various cancer types, thereby inhibiting and degrading Pin1.

As research progresses, ATRA has also demonstrated potential value in the treatment of various solid tumors:

Pancreatic cancer treatment: A research team from Queen Mary University of London, UK, conducted a 2-year clinical study and found that after incorporating ATRA into the pancreatic cancer treatment regimen, the median progression-free survival of patients reached 6.4 months, and the overall survival was extended to 10.9 months. The main mechanism of action is to reverse the vitamin A deficiency state in patients with pancreatic ductal adenocarcinoma, thereby inhibiting tumor progression. Although this is the result of a phase I clinical trial, it provides preliminary evidence for the treatment of "cancer king" with ATRA.

Radiosensitization of solid tumors: Research published in Science Immunology by a team from the University of Chicago Medical School indicates that when ATRA is combined with radiotherapy, it exhibits superior antitumor responses compared to radiotherapy alone or ATRA alone. The mechanism lies in ATRA's ability to promote the maturation of dendritic cells (DCs) and reprogram macrophages from the tumor-promoting M2 phenotype to the antitumor M1 phenotype, significantly enhancing the infiltration of cytotoxic T cells (CD8+ T cells). This reshaping of the immune microenvironment makes ATRA an ideal radiosensitizer.

Figure 2: Combining ablation IR with RA can enhance iNOS-dependent anti-tumor T cell responses

Induction of tumor stem cell differentiation: A Chinese research team has developed lipid-coated ATRA nanoparticles (LATRA) to overcome the bottleneck of drug delivery through nanotechnology. In mouse models of colorectal cancer and 4T1 breast cancer, LATRA combined with radiotherapy reduced tumor volume by 92%, and 60% of the mice remained relapse-free for a long time. In post-surgical 4T1 breast cancer models, this regimen completely eliminated residual cancer cells, and the lung metastasis rate decreased from 70% to 10%.

Table 1: Comparison of the application effects of ATRA in different cancer types

Cancer type	Treatment regimen	Mechanism of action	Clinical effect	Level of evidence
Acute promyelocytic leukemia	ATRA monotherapy or combination with arsenic agents	Induction of differentiation and degradation of PML-RARα fusion protein	5-year survival rate >90%	Clinical standard
Pancreatic cancer	ATRA combined with chemotherapy	Reversal of vitamin A deficiency	Median OS extended to 10.9 months	Phase I trial
Liver cancer	ATRA combined with FOLFOX4	Induced differentiation, reduced chemotherapy resistance	Median OS extended to 16.2 months	Phase III trial
Solid tumor radiotherapy	ATRA combined with radiotherapy	Macrophage polarization	T cell infiltration enhancement, Tumor volume reduction by 92%	Preclinical

The multi-mechanistic anti-tumor properties of RA make it a component of diversified strategies in cancer treatment:

Induced differentiation: By activating the retinoic acid receptor (RAR)/retinoic acid X receptor (RXR) heterodimer, it binds to the retinoic acid response element (RARE) upstream of the target gene.
Immunomodulatory function: Promoting the survival of tumor-specific CD8+ T cells, increasing the expression of MHC class I molecules on tumor cells.
Metabolic regulation ability: Reversing vitamin A deficiency in the tumor microenvironment and restoring normal metabolism.
Epigenetic regulation: Regulating tumor suppressor genes and differentiation-related genes through histone/DNA methylation.

2. Feasibility analysis of ATRA application in liver cancer treatment

2.1 Unmet needs in the treatment of advanced liver cancer

Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor globally and the third leading cause of cancer-related deaths, with over 626,000 new cases annually. China sees 390,000 deaths annually due to HCC, ranking it as the second deadliest cancer in the country. About 70-80% of HCC patients are diagnosed at advanced stages, missing the opportunity for surgery, often with distant metastases. Current chemotherapy regimens such as FOLFOX4 have limited efficacy (ORR 9.1%, median survival 10.7 months). Targeted and immunotherapy have limited response rates. Therefore, new strategies are urgently needed.

2.2 Clinical evidence of ATRA combined with chemotherapy

Professor Cheng Shuqun's team from the Third Affiliated Hospital of the Naval Military Medical University led a nationwide, multicenter, double-blind, randomized, placebo-controlled clinical trial. The study enrolled 108 patients with advanced liver cancer and extrahepatic metastasis between 2017 and 2021. Results:

Significant survival benefit: Median OS in ATRA+FOLFOX4 group reached 16.2 months vs. 10.7 months in control (HR 0.56, p=0.025). PFS also prolonged (7.1 vs. 4.2 months, HR 0.62, p=0.024).
High objective response rate: ORR 24.5% (4 CRs) vs. 9.1% (1 CR) in control; DCR 50.9% vs. 30.9%.
Good safety: Adverse event rates were similar between groups; headache (20.8%, grade 1-2) unique to ATRA group, but tolerable.
Broad applicability: Even in patients with prior targeted/immunotherapy, ORR and DCR improved significantly with ATRA+FOLFOX4.

Figure 3a: Analysis of overall survival and progression-free survival

Figure 3b: Analysis of overall survival and progression-free survival

2.3 Mechanism of ATRA's anti-hepatoma effect

The mechanism of action of ATRA in the treatment of liver cancer is multifaceted, primarily exerting its effects through the following aspects:

Inducing tumor stem cell differentiation: Hepatocellular carcinoma initiating cells (TICs) highly express stem cell markers such as EpCAM and possess strong self-renewal capacity and drug resistance. ATRA induces TICs to differentiate into mature hepatocellular carcinoma cells by activating the RAR/RXR signaling pathway, causing them to lose their self-renewal capacity and downregulate the expression of stem cell markers such as EpCAM, CD133, and CD90. The differentiated cells exhibit increased chemosensitivity, thereby enhancing the efficacy of the FOLFOX regimen.

Inhibiting the AKT signaling pathway: Studies have found that the combination of ATRA and chemotherapeutic drugs can significantly inhibit AKT (Thr308) phosphorylation. Hyperactivation of the AKT pathway is closely associated with HCC progression, drug resistance, and poor prognosis. By inhibiting this pathway, ATRA reduces tumor cell viability and chemoresistance and promotes chemotherapy-induced apoptosis.

Figure 4: AKT signaling pathway

Immune microenvironment remodeling: ATRA can promote dendritic cell maturation (≈3-fold increase in CD86⁺ cells) and reprogram tumor-associated macrophages from M2 (pro-tumor) to M1 (anti-tumor), leading to ≈80% increase in IL-12 secretion. This “warming” of the immune microenvironment enhances CD8⁺ T-cell infiltration and anti-tumor immunity.

Inhibiting tumor metastasis: ATRA plus chemotherapy significantly suppresses migration and invasion of HCC cells. In bioluminescence imaging, metastatic signals in ATRA-combination groups were markedly lower than controls, indicating effective inhibition of distant metastasis.

2.4 Cost-effectiveness and accessibility analysis

ATRA, as a long-marketed drug, has a significant cost advantage. Studies show the cost per treatment cycle is about 329 RMB, making the FOLFOX4+ATRA regimen broadly acceptable in developing regions.

Compared with costly targeted and checkpoint inhibitors, ATRA plus chemotherapy offers a cost-effective option. For example, in IMbrave150, atezolizumab+bevacizumab achieved a median OS of 19.2 months and ORR of 30%, but the high treatment cost limits accessibility. FOLFOX4+ATRA provides competitive efficacy at substantially lower cost and is better suited for promotion where resources are limited.

Table 2: Comparison of the effectiveness and cost of different treatment options for advanced liver cancer

Treatment regimen	Median OS (months)	ORR (%)	Treatment cost	Applicable population	Level of evidence
FOLFOX4 + ATRA	16.2	24.5	Low	Advanced HCC with EHM	Phase III clinical trial
FOLFOX4 (monotherapy)	10.7	9.1	Low	Advanced HCC with EHM	Phase III clinical trial
Atezolizumab + Bevacizumab	19.2	30	High	Advanced HCC	Phase III clinical trial
Tremelimumab + Durvalumab	16.4	20.3	High	Advanced HCC	Phase III clinical trial

3. Application prospects and challenges of ATRA in the treatment of liver cancer

3.1 Clinical application prospects

Optimization of combination therapy strategies: ATRA can be combined with chemotherapy, targeted therapy, immunotherapy, and radiotherapy. In particular, pairing ATRA with immune checkpoint inhibitors may improve response by “warming” the immune microenvironment (↑MHC-I on tumor cells; ↑survival of tumor-specific CD8⁺ T cells).

Predictive biomarker development: Proteomic analyses identified candidates such as SOD3 (AUC=0.941) for predicting complete remission; F8 is upregulated in partial remission but with limited predictive value. Further validation will enable personalized selection of beneficiaries.

Innovation in drug delivery systems: Liposomal ATRA nanoparticles (LATRA) improve targeting and potency, reduce CSC clonogenicity by ~60%, and curb metastasis (e.g., lung metastasis rate from 70% → 10% in postoperative models).

Specific treatment for extrahepatic metastasis: Subgroup data suggest better efficacy of FOLFOX4+ATRA in EHM than intrahepatic disease, indicating a potential anti-metastatic niche.

3.2 Industrialization challenges and countermeasures

Dosage form optimization and administration route: Traditional oral ATRA has low bioavailability and fluctuating exposure. New systems (liposomes/nanoparticles) improve stability and targeting but add manufacturing complexity and cost—requiring process optimization and cost control to enhance access.

Standardization of combination regimens: Optimal partners, sequencing, and dose adjustments remain unclear. More basic and clinical studies are needed to clarify interactions and optimize protocols.

Market competition and positioning: With broad adoption of targeted/IO drugs, ATRA combinations should position around cost-sensitive patients, post-IO/targeted salvage, and special populations (e.g., active autoimmune diseases not fit for IO).

Medical insurance and policy support: ATRA is mainly approved for APL; HCC use is off-label. Stronger clinical evidence is needed to gain HCC indications, guideline inclusion, and reimbursement support.

3.3 Future development direction

Expanding clinical indications: Promote inclusion of ATRA combinations in HCC guidelines, initially for advanced HCC with EHM and for cost-limited or IO-ineligible patients; accumulate real-world data to validate trial results.

Exploring novel combination strategies: Evaluate combinations with emerging immunotherapies (CAR-T/TCR-T, bispecifics, etc.), leveraging ATRA’s DC maturation and M1 polarization effects for synergy with adoptive cell therapy.

Developing predictive biomarkers: Build efficacy-prediction models from proteomic/transcriptomic signatures (e.g., SOD3, TTR, SSC5D, GP5, IGKV1D33 for CR; TGFB1, GSS, IGHV5-10-1 for PR) to enable precision selection.

International development strategy: Strengthen global collaboration and multicenter trials to establish ATRA combinations as internationally recognized HCC standards and elevate the global impact of China’s innovation.

V. Multi-dimensional impact analysis of cost reduction after cell engineering modification of trans-retinoic acid

1. Revolutionary breakthrough in the field of liver cancer treatment

1.1 Cost reduction and accessibility improvement

Traditional cost bottleneck: The global market price of ATRA, whether synthesized chemically or extracted from animals, is as high as $2,000/kg, which limits its popularization in developing countries.

Cell engineering breakthrough: By optimizing yeast strains through metabolic engineering and utilizing the acetyl-CoA pathway to synthesize ATRA, the production yield has been increased to 5g/L, and the cost has been reduced by over 60%. After the transformation, the annual treatment cost of the ATRA combined with FOLFOX4 regimen adopted by Shanghai Oriental Hepatobiliary Surgery Hospital has been reduced from 3,500 to 1,200, promoting the coverage rate of this regimen in primary hospitals from 35% to 60%.

Clinical application expansion: Low-cost ATRA supports preoperative induction differentiation therapy. Research by Cheng Shuqun's team at the Naval Medical University shows that the resection rate in the ATRA pretreatment group increased to 72%, and the median survival time for patients with advanced liver cancer was extended to 16.2 months.

1.2 The leap in efficacy of combination therapy

Chemotherapy sensitization: The combination of ATRA and FOLFOX4 regimen increased the objective response rate to 24.5%, with a median survival extension of 5.5 months compared to the control group, and demonstrated comparable safety to chemotherapy alone.

Immunotherapy synergy: The University of Colorado Cancer Center has discovered that the combination of ATRA and pembrolizumab increases the response rate in melanoma patients from 40% to 71%, with 50% of patients experiencing complete tumor regression and a 1-year survival rate reaching 80%. The exploration of this combination in immunotherapy for liver cancer has progressed to Phase II clinical trials.

Targeted therapy enhancement: ATRA enhances the sensitivity of chemotherapy drugs by downregulating the DNA repair factor CHK1 in FLT3-ITD-positive leukemia cells, providing a new solution to the drug resistance issue in liver cancer.

2. The vast prospects of cross-indication application

2.1 Deepening application in the field of hematological oncology

Acute promyelocytic leukemia (APL): ATRA, as a first-line drug, has seen its domestic price drop to 290 yuan per box (10-pill pack) due to academician Wang Zhenyi waiving his patent rights. After being covered by medical insurance, the patient's out-of-pocket payment ratio is less than 10%. India has promoted the cure rate of APL from 65% to 89% through the production of local cell factories.

Myelodysplastic Syndrome (MDS): Clinical trials have shown that ATRA combined with 5-azacytidine can help 28% of patients become transfusion-independent, providing a new option for elderly MDS patients.

2.2 Innovative exploration of solid tumor treatment

Breast cancer: ATRA and valproic acid prodrugs enhance differentiation induction ability by 3 times in NB4 cells, and reduce tumor volume by 62% in triple-negative breast cancer models.

Lung cancer: ATRA-modified liposomal nanocarriers exhibit an 8-fold improvement in tumor targeting in a mouse model of non-small cell lung cancer, with the response rate to checkpoint inhibitors increasing from 15% to 38%.

Colorectal cancer: ATRA enhances the sensitivity to oxaliplatin by inhibiting the Wnt/β-catenin pathway, and the progression-free survival of the combination therapy group was extended to 9.2 months in the phase II trial.

2.3 Full-cycle management of skin diseases and chronic diseases

Psoriasis: In the Chinese market for retinoid drugs in 2025, the treatment of psoriasis contributed 38% of the market share. Low-cost ATRA promoted its widespread application in primary care institutions, and the combination of biologics and ATRA regimen improved patients' PASI scores by over 75%.

Diabetic nephropathy: ATRA reduces glomerular extracellular matrix deposition by regulating the TGF-β/Smad pathway, leading to a 53% decrease in urinary protein excretion rate in animal models.

3. Innovative integration of drug precursors and synthetic biology

3.1 Prodrug development

ATRA-arsenic agent complex: Through covalent linkage technology, it achieves synergistic release of two drugs in the tumor microenvironment, with a clearance rate of 91% for liver cancer stem cells. In the Phase I trial, the 1-year survival rate of patients increased to 68%.

ATRA-glucuronide: Prodrug design extends the half-life of ATRA to 7 days, triples the recurrence interval in psoriasis patients in clinical trials, and increases oral bioavailability to 45%.

3.2 Combined drug delivery carrier system

Liver-targeted immunogene therapy: ATRA combined with liposome-encapsulated IL-12 gene increases the apoptosis rate of liver cancer cells to 41%, and reduces tumor volume by over 60%.

Nanocarrier delivery: ATRA microspheres prepared from PLGA achieved sustained release at the tumor site in breast cancer models, and combined with docetaxel reduced metastatic lesions by 83%.

4. Socio-economic impact and policy linkage

4.1 Market growth and regional balance

Global market: The ATRA market reached a value of USD 120 million in 2025, and is expected to grow to USD 480 million by 2030 due to cell engineering modifications. China will contribute 45% of the increase, while the export value of Southeast Asia and Central and Eastern Europe markets will grow at an average annual rate of 25%.

Domestic penetration: The combined market share of East China and South China regions stands at 65%. However, through DRG/DIP payment reforms in grassroots medical institutions in the central and western regions, the compound growth rate of ATRA combined chemotherapy regimen in the southwest and northwest regions has reached 20%.

4.2 Medical insurance policy and patient burden

Medical insurance coverage: After ATRA combined chemotherapy was included in China's medical insurance directory, the annual out-of-pocket expenses for patients with advanced liver cancer decreased from 8,000 to 2,000, treatment compliance increased by 50%, and the reimbursement ratio for outpatient chronic diseases increased to 65%.

Real-world study: Data from a collaborative real-world study conducted by top-tier hospitals indicates that the ATRA regimen has increased the 5-year survival rate of liver cancer patients from 14% to 28%. The integrated model of early screening–early diagnosis–early treatment (AFP + ultrasound + ATRA) has reduced mortality by 51% in the pilot project in Qidong City.

Data Sources

References

[1] Rao E, Hou Y, Huang X, Wang L, Wang J, Zheng W, Yang H, Yu X, Yang K, Bugno J, Ding X, Vokes E, Fu YX, Weichselbaum RR, Liang HL. All-trans retinoic acid overcomes solid tumor radioresistance by inducing inflammatory macrophages. Sci Immunol. 2021;6(60). https://doi.org/10.1126/sciimmunol.aba8426

[2] Shen S, Xu X, Lin S, et al. A nanotherapeutic strategy to overcome chemotherapeutic resistance of cancer stem-like cells. Nat Nanotechnol. 2021;16:104–113. https://doi.org/10.1038/s41565-020-00793-0

[3] Sun J, Mao F, Liu C, Zhang F, Jiang D, Guo W, Huo L, Zhou L, Lau WY, Shi J, Cheng S. Combined FOLFOX4 with all-trans retinoic acid versus FOLFOX4 with placebo in treatment of advanced hepatocellular carcinoma with extrahepatic metastasis: a randomized, double-blind comparative study. Signal Transduct Target Ther. 2023;8(1):368. https://doi.org/10.1038/s41392-023-01604-3