Lentinan and Chemotherapy: Synergistic Effects on Survival

Shiitake Mushrooms

48% improvement in treatment response rate: lentinan + chemotherapy vs. chemotherapy alone

A 2024 systematic review and meta-analysis of 31 randomized trials (2,729 patients) found that injectable lentinan combined with chemotherapy improved treatment response rates with a relative risk of 1.48 compared to chemotherapy alone. The same analysis found improved quality of life and reduced chemotherapy toxicity, and a separate individual-patient meta-analysis found a survival benefit in advanced gastric cancer.

Wang et al., 2024

689 vs 565 days

median overall survival for gastric cancer patients receiving lentinan plus S-1 chemotherapy vs. S-1 alone (p=0.04); five-year survival 10% vs 0% in that cohort (Ina et al., 2011)

HR 0.80

pooled hazard ratio for overall survival with lentinan plus chemotherapy vs. chemotherapy alone in advanced gastric cancer, across five randomized trials (Oba et al., 2009)

Lung cancer too

a meta-analysis of lentinan plus chemotherapy for non-small cell lung cancer improved objective response (RR 1.31) and cut grade III/IV toxicity, not only for gastric cancer (Yin et al., 2015)

Wang et al., 2024

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Lentinan is one of only two mushroom-derived compounds (alongside PSK from turkey tail) with an approved cancer drug status in Japan. It has been used as an injectable cancer adjuvant there since the 1980s, combined with standard chemotherapy regimens for gastric cancer. Decades later, the evidence base has grown to include multiple meta-analyses covering thousands of patients, and the benefit signal remains consistent: lentinan adds meaningful survival benefit to chemotherapy while simultaneously reducing the severity of chemotherapy's adverse effects.

The mechanism behind this dual benefit connects directly to the underlying biology. Chemotherapy kills cancer cells directly through cytotoxic mechanisms. Lentinan activates immune surveillance through T-cell and NK-cell recruitment, attacking the tumor through a complementary pathway. The same lentinan-induced MAPK pathway activity that modulates immune function also suppresses inflammatory signaling, providing the protective effect against chemotherapy toxicity. For the broader context of shiitake's bioactive compounds, see what is shiitake mushroom: the culinary mushroom with medicinal power.

Clinical Meta-Analyses · Lentinan + Chemotherapy

What the Pooled Trials Show, Across Two Cancers

Four peer-reviewed meta-analyses of injectable lentinan added to chemotherapy. Efficacy favors the combination in every one; three of the four also report reduced chemotherapy toxicity. Values are pooled effect estimates from the source papers.

Meta-analysis	Cancer	Evidence base	Efficacy signal	Toxicity signal
Wang 2024[1]	Gastric	31 RCTs · 2,729 pts	RR 1.48treatment response (95% CI 1.36–1.61)	↓ WBC, GI & platelet decline
Oba 2009[2]	Gastric (advanced)	5 RCTs · 650 IPD	HR 0.80overall survival (95% CI 0.68–0.95)	not pooled
Yin 2015[5]	NSCLC (lung)	12 studies · 950 pts	RR 1.31objective response (95% CI 1.14–1.52)	↓ gr III/IV GI (RR 0.54) & granulocytopenia (RR 0.65)
Zhang 2018[7]	Lung	38 RCTs · 3,117 pts	56.9% vs 43.3%mean objective response (p < 0.001)	rare hypotension / allergy (case reports)

RR > 1 and HR < 1 both favor lentinan + chemotherapy. These are the pooled clinical meta-analyses; the single-cohort Ina 2011 survival detail is shown separately below. Meta-analyses of predominantly Chinese and Japanese hospital trials carry publication-bias and quality caveats the source papers discuss — the direction of benefit is consistent, the precise magnitude less certain.

The 2024 Meta-Analysis: Most Comprehensive Evidence to Date

Wang and colleagues (2024) published a systematic review and meta-analysis specifically on injectable lentinan combined with chemotherapy for gastric cancer, covering 31 randomized controlled trials with 2,729 patients.^[1]

The key finding: lentinan combined with chemotherapy produced a relative risk of 1.48 (95% CI: 1.36-1.61) for treatment response rate compared to chemotherapy alone. In plain terms, patients receiving the combination were about 48% more likely to show treatment response than patients receiving chemotherapy alone. The analysis also found improvements in immune markers (CD3+, CD4+, and CD4+/CD8+ ratios and natural killer cells) and in quality of life (RR 1.32).

Importantly, the 2024 meta-analysis did not report an overall-survival endpoint; its efficacy signal is treatment response, immune function, and quality of life. The meta-analytic approach (combining data from 31 separate trials, with trial sequential analysis and GRADE assessment rating the evidence "high" or "moderate") provides a stronger evidence level for this combination than any single study could offer.

The survival question is answered by a separate analysis. Oba and colleagues (2009) performed an individual-patient-data meta-analysis of five centrally randomized trials in advanced gastric cancer, pooling 650 patients.^[2] Adding lentinan to chemotherapy significantly prolonged overall survival, with a pooled hazard ratio of 0.80 (95% CI: 0.68-0.95, p=0.011) and no heterogeneity between trials. A hazard ratio of 0.80 corresponds to a 20% lower risk of death over follow-up for the lentinan combination.

The toxicity side of the ledger is where the 2024 meta-analysis is most concrete: lentinan reduced the incidence of white-blood-cell decline, gastrointestinal reactions, and platelet decline, and the authors reported no serious adverse effects attributable to lentinan. This matters clinically. Chemotherapy causes side effects that limit tolerable doses, interrupt treatment schedules, and degrade quality of life. An adjuvant that lowers hematologic and gastrointestinal toxicity addresses a major limitation of chemotherapy, independent of any direct anti-cancer benefit.

The Survival Numbers: What They Mean in Practice

Abstract percentage improvements and relative risks become concrete when translated into actual survival durations. Ina and colleagues (2011) reported these numbers for gastric cancer patients receiving lentinan plus S-1 chemotherapy versus S-1 alone.^[3]

S-1 is an oral fluoropyrimidine chemotherapy drug widely used for gastric cancer in Japan. This study was a single-center cohort comparison, not a randomized trial: 78 patients with metastatic or recurrent gastric cancer received S-1-based first-line chemotherapy, and outcomes were compared between the group that also received injectable lentinan and the group that did not. That design carries a real risk of selection bias, so the numbers below are best read as a strong signal rather than randomized-trial-grade proof.

Ina 2011 · Survival Over Time

Survival Rates: Lentinan + S-1 vs. S-1 Chemotherapy Alone

Percent of patients alive at each timepoint in the Ina 2011 cohort (31 received lentinan + S-1; 37 received S-1 alone). The widest gap is at 5 years, where 10% of the lentinan group survived versus none of the chemotherapy-alone group — a striking result from one modest, non-randomized cohort.

Lentinan + S-1S-1 alone

A cohort study, not a randomized trial: patient selection and the small sample size add uncertainty, so the gap reflects an association rather than proof that lentinan alone produced it. Median overall survival was 689 vs. 565 days (p = 0.0406).

Source: Ina et al., World Journal of Clinical Oncology (2011), 2(10):339-43 [ref 3], RTHM-00404 (PMID 21994907). Survival rates quoted verbatim from the full text.

Median overall survival: 689 days (lentinan + S-1) versus 565 days (S-1 alone). This represents roughly four additional months of median overall survival for the lentinan combination. The p-value was 0.04, indicating a statistically significant difference in this cohort.

Five-year survival: the study reported 10% in the lentinan plus S-1 group versus 0% in the S-1 alone group. No patient in the chemotherapy-alone group survived to five years in this cohort, while roughly one in ten of the lentinan combination group did.

Ina and colleagues published a follow-up study in 2016 specifically examining gastric cancer patients with liver metastases, a particularly high-risk population.^[6] Even in this advanced disease setting, the chemoimmunotherapy combination produced measurable survival benefit compared to chemotherapy alone.

Why the Combination Works Better Than Either Alone

The mechanistic explanation for lentinan's synergy with chemotherapy is a "two-mechanism attack on the tumor" story.

Chemotherapy operates through direct cytotoxicity: drugs like S-1 and cisplatin interfere with DNA synthesis and cellular division, causing cancer cells to die. This mechanism is effective but non-specific; normal cells are also harmed, producing the adverse effects associated with cancer treatment.

Lentinan operates through immune activation. Its beta-1,3-glucan structure is recognized by pattern recognition receptors on immune cells (including Dectin-1, TLR2, and CR3). This recognition triggers dendritic cell maturation, which in turn primes CD8+ cytotoxic T cells and activates NK cells to recognize and attack tumor cells directly. The anti-tumor immune response that lentinan promotes is additive to chemotherapy's direct killing.

The combination produces greater tumor elimination than either alone because two independent mechanisms are attacking the same tumor. Cancer cells that survive chemotherapy can be targeted by lentinan-activated immune cells, and vice versa. This complementary action is the fundamental reason the meta-analyses consistently show benefit from the combination.

The Adverse Event Reduction Mechanism

The toxicity reductions seen across the meta-analyses are not only a quality-of-life benefit. The 2024 gastric-cancer analysis reported fewer episodes of white-blood-cell decline, gastrointestinal reactions, and platelet decline,^[1] and the lung-cancer meta-analysis found lentinan roughly halved grade III/IV gastrointestinal toxicity (RR 0.54) and cut grade III/IV granulocytopenia (RR 0.65).^[5] This pattern reflects lentinan's anti-inflammatory activity operating through a distinct molecular pathway.

Xu and colleagues (2012) investigated the mechanism by which lentinan suppresses inflammation at the molecular level, finding that beta-glucan from Lentinus edodes inhibits nitric oxide and TNF-alpha production and suppresses phosphorylation of mitogen-activated protein kinases (MAPK) in macrophages stimulated with lipopolysaccharide.^[4]

Chemotherapy causes significant inflammation in treated tissues: mucositis (inflammation of the mouth and GI tract), neuropathy (nerve inflammation), and other adverse effects are driven in part by inflammatory signaling. Lentinan's MAPK pathway suppression reduces the inflammatory component of these adverse effects, not the direct cellular damage from the chemotherapy drug but the inflammatory amplification that turns initial damage into severe symptoms.

This dual action (immune stimulation for anti-tumor effect + inflammation suppression for toxicity protection) positions lentinan as a particularly well-suited cancer adjuvant: it improves efficacy while protecting patients from the treatment's harms.

Beyond Gastric Cancer: Lung Cancer Meta-Analysis

The Japanese clinical trials of lentinan focused primarily on gastric cancer, reflecting the historical development context. But the biological mechanism for lentinan's benefit is not gastric-specific: immune activation and MAPK-mediated inflammation suppression operate across cancer types.

Yin and colleagues (2015) published a meta-analysis of 12 clinical studies (950 patients) examining lentinan injection combined with chemotherapy for non-small cell lung cancer (NSCLC).^[5] The pooled objective response rate was significantly higher with the combination (RR 1.31, 95% CI: 1.14-1.52), and chemotherapy-related grade III/IV gastrointestinal reactions (RR 0.54) and grade III/IV granulocytopenia (RR 0.65) were both significantly reduced. The same dual pattern seen in gastric cancer, better response plus lower toxicity, appears again in lung cancer.

A larger review by Zhang and colleagues (2018) surveyed 12 years of Chinese lentinan lung-cancer trials, pooling 38 randomized studies with 3,117 patients.^[7] It reported a mean objective response of 56.9% with lentinan plus chemotherapy versus 43.3% with chemotherapy alone (p<0.001). The authors were candid about the limits of this literature: adverse-event data were not pooled across trials, survival endpoints were weak, and most trials used hospital-prepared lentinan, so the finding is a short-term response signal rather than proof of a survival benefit.

This matters for understanding lentinan's place in cancer adjuvant medicine: it is not a gastric-specific compound whose benefit happens to have been tested there. The mechanism is general enough to produce a consistent short-term benefit in at least two different cancer types across meta-analytic evidence, even as the strength of that evidence varies by endpoint.

The Immunotherapy Angle: Theoretical Synergy with Checkpoint Inhibitors

The most forward-looking question in lentinan cancer research is whether it might synergize with modern immunotherapy drugs, specifically PD-1/PD-L1 checkpoint inhibitors like pembrolizumab, nivolumab, and atezolizumab.

Checkpoint inhibitors work by removing the molecular brakes that tumors place on T cells. Tumors express PD-L1 to suppress T cell activity; drugs that block this suppression allow T cells to remain active against the tumor. The effect is most pronounced in patients who have T cells already primed against their tumors.

Lentinan's mechanism creates exactly those conditions: it activates T cells and shifts the immune response toward Th1 (anti-tumor). If lentinan-treated patients have more active T cells that are more primed against their tumors, checkpoint inhibitors that remove the T cell suppression signal may have a larger T cell reservoir to work with.

This synergy hypothesis is plausible from first principles and consistent with lentinan's mechanism. No randomized trial has tested lentinan plus checkpoint inhibitors. The hypothesis generates a testable clinical research question: does adding lentinan to PD-1/PD-L1 therapy improve outcomes compared to checkpoint inhibitor alone? This is the frontier of lentinan research, not the established evidence.

This article summarizes clinical research and is not medical advice. The evidence discussed here comes from studies of injectable, pharmaceutical-grade lentinan administered under oncologist supervision, not from over-the-counter shiitake or mushroom supplements. Anyone undergoing cancer treatment should make decisions about adjuvant therapies only in consultation with their oncology team.

The Bottom Line

Lentinan combined with injectable chemotherapy produces a consistent benefit across multiple meta-analyses. A 2024 meta-analysis of 31 trials (2,729 patients) found a 48% improvement in treatment response rate (RR 1.48), better immune markers and quality of life, and reduced chemotherapy toxicity (Wang et al.). A separate individual-patient meta-analysis of five trials (650 patients) found prolonged overall survival in advanced gastric cancer, HR 0.80 (Oba et al., 2009). The Ina et al. (2011) cohort showed 689 vs 565 days median overall survival with 10% vs 0% five-year survival, though as a non-randomized cohort it is a signal rather than proof. Benefit extends to lung cancer (Yin et al., 2015; Zhang et al., 2018), where response improved and grade III/IV toxicity fell. The mechanism is complementary: lentinan activates immune surveillance while suppressing MAPK-mediated inflammation (Xu et al., 2012), addressing both the anti-tumor and anti-toxicity dimensions. Checkpoint-inhibitor synergy remains theoretical.

Frequently Asked Questions

Why does lentinan work better with chemotherapy?

Lentinan and chemotherapy attack cancer through complementary mechanisms that combine synergistically. Chemotherapy directly kills cancer cells through DNA damage and cell division disruption. Lentinan activates the immune system's cancer surveillance: it primes T cells and NK cells to attack tumor cells through immune recognition. Together, they produce greater tumor reduction than either alone. Additionally, lentinan's MAPK anti-inflammatory activity reduces the severe adverse effects of chemotherapy, allowing treatment to proceed more effectively.

Which chemotherapy drugs work with lentinan?

The most documented combination is injectable lentinan with S-1 (an oral fluoropyrimidine) for gastric cancer, which produced the specific survival data from Ina et al. (2011): 689 vs. 565 days median OS. Wang et al.'s 2024 meta-analysis pooled 31 randomized trials covering multiple chemotherapy combinations, and the pooled survival analysis by Oba et al. (2009) spanned five randomized S-1 and other regimens. Benefit has been documented with S-1-based and platinum-based regimens in gastric cancer, and separate lung-cancer meta-analyses (Yin et al., 2015; Zhang et al., 2018) documented benefit with NSCLC chemotherapy regimens.

Does lentinan reduce chemotherapy side effects?

Yes, with documented evidence. Wang et al.'s 2024 meta-analysis of 31 gastric-cancer trials found lentinan reduced the incidence of white-blood-cell decline, gastrointestinal reactions, and platelet decline. In lung cancer, Yin et al.'s 2015 meta-analysis found lentinan roughly halved grade III/IV gastrointestinal toxicity (RR 0.54) and cut grade III/IV granulocytopenia (RR 0.65). The likely mechanism is lentinan's suppression of MAPK-pathway phosphorylation (Xu et al., 2012), which dampens the inflammatory component of chemotherapy adverse effects without impairing the drug's direct cancer-killing action.

How does lentinan enhance cancer treatment?

Through two simultaneous mechanisms. The anti-tumor mechanism: lentinan activates dendritic cells via Dectin-1, TLR2, and CR3 pattern recognition; matured dendritic cells prime CD8+ cytotoxic T cells and activate NK cells that attack cancer cells directly. This immune activation is additive to chemotherapy's direct cytotoxicity. The toxicity protection mechanism: lentinan suppresses MAPK-mediated inflammatory signaling (Xu et al., 2012), reducing the inflammatory amplification of chemotherapy's direct cellular damage that produces severe adverse effects.

Can lentinan be used with modern immunotherapy drugs?

No clinical trial has tested lentinan combined with checkpoint inhibitors (PD-1/PD-L1 drugs like pembrolizumab or nivolumab). The theoretical case for synergy is plausible: lentinan activates T cells and shifts immune response toward Th1; checkpoint inhibitors remove the molecular brakes that tumors place on those T cells; having more active T cells available when the brakes are removed might amplify checkpoint inhibitor benefit. This is a hypothesis for clinical research, not established practice. Discuss any supplement use during immunotherapy with your oncologist.

Sources & References

1. 1RTHM-02015·Wang, Yixuan et al. (2024). “Systematic review and meta-analysis on the efficacy and safety of Injectable Lentinan combined with chemotherapy in the treatment of gastric cancer..” Phytomedicine : international journal of phytotherapy and phytopharmacology.Study breakdown →PubMed →↩
2. 2RTHM-00313·Oba, Koji et al. (2009). “Individual patient based meta-analysis of lentinan for unresectable/recurrent gastric cancer..” Anticancer research.Study breakdown →PubMed →↩
3. 3RTHM-00404·Ina, Kenji et al. (2011). “Lentinan prolonged survival in patients with gastric cancer receiving S-1-based chemotherapy..” World journal of clinical oncology.Study breakdown →PubMed →↩
4. 4RTHM-00272·Xu, Xiaojuan et al. (2012). “β-Glucan from Lentinus edodes inhibits nitric oxide and tumor necrosis factor-α production and phosphorylation of mitogen-activated protein kinases in lipopolysaccharide-stimulated murine RAW 264.7 macrophages..” The Journal of biological chemistry.Study breakdown →PubMed →↩
5. 5RTHM-00752·Yin, X et al. (2015). “A meta-analysis of lentinan injection combined with chemotherapy in the treatment of nonsmall cell lung cancer..” Indian journal of cancer.Study breakdown →PubMed →↩
6. 6RTHM-00787·Ina, Kenji et al. (2016). “Chemo-Immunotherapy Using Lentinan for the Treatment of Gastric Cancer with Liver Metastases..” Medical sciences (Basel.Study breakdown →PubMed →↩
7. 7RTHM-00538·Zhang, Yiran et al. (2018). “Lentinan as an immunotherapeutic for treating lung cancer: a review of 12 years clinical studies in China..” Journal of cancer research and clinical oncology.Study breakdown →PubMed →↩