Immunotherapy has revolutionized the treatment of cancer. However, microsatellite stable (MSS) metastatic colorectal cancer (mCRC) shows a low response to PD-1 inhibitors. Antiangiogenic therapy can enhance anti-PD-1 efficacy, but it still cannot meet clinical needs. Increasing evidence supported a close relationship between gut microbiome and anti-PD-1 efficacy. This study aimed to explore the efficacy and safety of the combination of fecal microbiota transplantation (FMT) and tislelizumab and fruquintinib in refractory MSS mCRC. In the phase II trial, MSS mCRC patients were administered FMT plus tislelizumab and fruquintinib as a third-line or above treatment. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR), clinical benefit rate (CBR), safety and quality of life. Feces and peripheral blood were collected for exploratory biomarker analysis. This study is registered with Chictr.org.cn, identifier ChiCTR2100046768. From May 10, 2021 to January 17, 2022, 20 patients were enrolled. Median follow-up was 13.7 months. Median PFS was 9.6 months (95% CI 4.1–15.1). Median OS was 13.7 months (95% CI 9.3–17.7). Median DoR was 8.1 months (95% CI 1.7–10.6). ORR was 20% (95% CI 5.7–43.7). DCR was 95% (95% CI 75.1–99.9). CBR was 60% (95% CI 36.1–80.9). Nineteen patients (95%) experienced at least one treatment-related adverse event (TRAE). Six patients (30%) had grade 3–4 TRAEs, with the most common being albuminuria (10%), urine occult blood (10%), fecal occult blood (10%), hypertension (5%), hyperglycemia (5%), liver dysfunction (5%), hand-foot skin reaction (5%), and hypothyroidism (5%). No treatment-related deaths occurred. Responders had a high-abundance of Proteobacteria and Lachnospiraceae family and a low-abundance of Actinobacteriota and Bifidobacterium. The treatment did not change the structure of peripheral blood TCR repertoire. However, the expanded TCRs exhibited the characteristics of antigen-driven responses in responders. FMT plus tislelizumab and fruquintinib as third-line or above treatment showed improved survival and manageable safety in refractory MSS mCRC, suggesting a valuable new treatment option for this patient population. This study was supported by the 10.13039/501100001809 National Natural Science Foundation of China (82102954 to Wensi Zhao) and the 10.13039/501100018570 Special Project of Central Government for Local Science and Technology Development of Hubei Province (ZYYD2020000169 to Yongshun Chen).

Accumulating evidence supports the existence of cancer stem cells (CSCs) in human tumors, and the successful certification of CSCs may lead to the identification of therapeutic targets, which are more effective for the treatment of cancer. The use of spherical cancer models has increased in popularity in cancer stem cell investigations. Tumorospheres, which are used as a model of CSCs and are established in serum‑free medium supplemented with growth factors under non‑adherent conditions, are one of the most commonly used cancer spherical models and are a valuable method for enriching the CSC fraction. To investigate whether this model is applicable in lung cancer (LC), the identification of lung CSCs and their capacities is essential. In the present study, lung CSCs were enriched by sphere-forming culturing and their stem‑like properties were assessed. The results indicated that the lung tumorospheres had enhanced proliferation, clonality, invasion and cisplatin‑resistance, and showed significantly increased expression levels of CD133 and breast cancer resistance protein (ABCG2). These results, together with findings previously reported in literature, indicated that the sphere‑forming culturing of LC cells induced the enrichment of CSCs and that the tumorospheres exhibited stem cell characteristics. In addition, the higher expression levels of CD133 and ABCG2 in the tumorospheres may provide a rationale for therapeutic targets for LC.

Background: Immune checkpoint inhibitor (ICI) has reshaped the treatment landscape of esophageal squamous cell carcinoma (ESCC). But most patients end up with disease progression and/or therapeutic intolerance. The subsequent ICI rechallenge raises some discussions.Methods: A retrospective study was conducted to assess the efficacy and safety of reintroduction of ICI in patients with advanced or metastatic ESCC after first‐line ICI failure. Outcomes included median overall survival (OS), progression‐free survival (PFS), objective response rate (ORR), disease control rate (DCR) and safety. Subgroup analysis and prognostic analysis were also performed.Results: A total of 1320 patients were screened and 138 were enrolled: 109 received second‐line ICI‐based therapies, and 29 received non‐ICI therapies. As of data cutoff on November 30, 2024, patients with ICI rechallenge, compared with non‐ICI rechallenge, achieved an improved second‐line OS (10.4 vs. 5.8 months; HR = 0.53, 95% CI: 0.33–0.84; p = 0.006) and showed a favorable PFS trend (5.0 vs. 3.0 months; HR = 0.75, 95% CI: 0.48–1.17; p = 0.202). The 6‐month PFS rate was 42.9% versus 22.3%, and the 12‐month OS rate was 41.5% versus 23.2%, respectively. The ORR was 30.3% versus13.8% and the DCR was 79.8% versus 58.6%, respectively. ICI combined with chemoradiotherapy was the most popular option for subsequent ICI rechallenge, with an OS of 11.2 months. Treatment‐related adverse events of grade ≥ 3 occurred in 47 (43.1%) and 11 (37.9%) patients in the two groups.Conclusion: Second‐line ICI rechallenge provided OS benefits in advanced or metastatic ESCC, with manageable safety. Further prospective study is warranted.

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