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作者最怕哪种审稿意见？一定是和实验设计相关的。这类问题不仅涉及实验本身，改起来难度大，回复得不好，还可能导致拒稿。那么，面对审稿人的犀利质疑，作者该如何巧妙应对？

本期，我们结合Nature近期发表论文的回复信，看看作者如何回复关于实验的提问，最终赢得审稿人认可的~

1 样本选择不合适，怎么回复？

审稿人：指出作者选的研究样本并不符合实验设定的两个年龄区间，语气也比较严厉。

I am seriously not certain why you decided to present a ERBB2 case who was a 52 yo M. As your paper was a comparison between 20-40 and 60-80, this patient should have been included to begin with? What happened? Didn't you have better examples?

我真的不确定你为什么决定提出一个52岁的ERBB2病例，因为你的论文是20-40和60-80之间的比较，这个病人应该被包括在内吗？发生了什么事?你没有更好的例子吗？

作者回复思路：

第一步 解释了选择这个样本的原因，介绍了215个实验病例的具体情况，说明没有完全符合要求的样本病例。

……The reasons were mainly as follows. Among the 215 recruited YG patients with lung adenocarcinoma in our retrospective cohort, 44 patients possessed ERBB2 mutations. Early-stage patients accounted for the vast majority, without any relapse after surgery. ……As for the three IV-stage patients, two patients didn’t receive the pyrotinib targeted therapy because treatment course occurred before pyrotinib was approved in China, and one patient regretfully gave up treatment due to personal reasons. Therefore, we did not find suitable patients from this retrospective cohort to validate the new findings.

......原因主要有以下几点。在我们的回顾性队列中招募的215例YG肺腺癌患者中， 44例患者具有ERBB2突变。早期患者占绝大多数，术后无复发......在这3例iv期患者中，有2例患者因为疗程发生在pyrotinib在中国获批之前，而没有接受pyrotinib靶向治疗，1例患者因个人原因遗憾放弃治疗。因此，我们没有从回顾性队列中找到合适的患者来验证新发现。

第二步 进一步解释了选择该样本的合理性，即使年龄不完全匹配，但也符合研究逻辑。强调研究关注的是ERBB2突变，而不是单纯年龄因素。

New patients need to be recruited for the validation purpose with several criteria (See Methods section – “Patient treatment with pyrotinib”). …… The 52-year-old male patient just met these criteria although the age on diagnosis was not strictly fallen in between 20-40 but still relatively young compared to most of other patients.  ……Moreover, the underlying logic for HER2-targeted therapy is whether ERBB2 mutation is the main driver of the tumorigenesis but not just the age itself. 

新招募的患者需要满足几个标准（见方法部分-“患者使用pyrotinib治疗”）......这位52岁的男性患者正好符合这些标准，尽管诊断时的年龄并没有严格落在20-40岁之间，但与大多数其他患者相比，仍然相对年轻。......此外，her2靶向治疗的潜在逻辑是ERBB2突变是否是肿瘤发生的主要驱动因素，而不仅仅是年龄本身。

第三步 提出改进方案：增加一例符合要求的样本，并补充了实验数据和结果（图文并茂）。

To strengthen this part, following the reviewer’s suggestion, we further presented another 33-year-old (on diagnosis) female patient with lung adenocarcinoma recruited from our branch hospital, who is currently undergoing treatment. …… After receiving oral pyrotinib targeted treatment for 6 months, she achieved sustained disease remission with rapid decrease of metastatic nodules in tumor size (Newly added Fig. 5h-j). Results from the two cases were quite encouraging.

为了加强这部分内容，根据审稿人的建议，我们进一步提交了另一名来自我院分院的33岁（确诊）肺腺癌女性患者，目前正在接受治疗。......经口服吡罗替尼靶向治疗6个月后，患者病情持续缓解，肿瘤转移结节大小迅速减少（新增图5h-j）。这两个案例的结果相当令人鼓舞。

2 实验结果不可靠

审稿人：The immunological analysis part also requires particularly sophisticated experiments and analysis techniques. Since this can vary greatly depending on not only age but also tumor size and location of examined tumor area, the results of data obtained using heterogeneous patient groups and specimens can be said to be unreliable.

免疫学分析部分需要特别复杂的实验和分析技术。这不仅取决于年龄，还取决于肿瘤大小和检查肿瘤区域的位置，因此使用异质患者群体和标本获得的数据结果可以说是不可靠的。

作者回复思路：

作者没有回避这个问题，而是从两个方面积极提出了改进方案：

一是扩大匹配样本量，消除可能的影响因素。

……

Following the reviewer’s suggestion, we removed the bias from these factors by performing PSM adjustment and found similar conclusions with 116 matched samples (Newly added Supplementary Table 7; Newly added Supplementary Fig. 4). These efforts with large quantities of samples should have minimized the unreliability in such analysis with heterogeneous patient groups and specimens.

……根据审稿人的建议，我们通过PSM调整消除了这些因素的偏倚，并在116个匹配样本中发现了相似的结论(新增补充表7、图4)。这些大量样本的工作应该最小化了这种对异质患者群体和样本的分析的不可靠性。

二是，通过引入另一种更复杂的检验技术印证结论，综合证明自己的结论真实可靠。

Furthermore, following your suggestion, we employed another sophisticated technique - multiplex immunofluorescence to re-examine 20 representative PSM matched samples.……Taken together, our results reliably indicated that lung cancer from YG patients tends to possess a relatively suppressive tumor microenvironment compared to that of EG patients.

此外，根据您的建议，我们采用了另一种复杂的技术-多重免疫荧光重新检查了20个具有代表性的PSM匹配样本……综上所述，我们的研究结果可靠地表明，与EG患者相比，YG患者的肺癌往往具有相对抑制性的肿瘤微环境。

尽管审稿人指出仍存在样本量不足的问题，但认可了作者的努力，并给予了积极评价，论文顺利通过审稿。

3 经验总结

对于审稿人对于实验设计方面的质疑，切忌硬碰硬地反驳，而是抓住审稿人的心理，提供合理的解释和有效的改进措施。

下面几点最能打动审稿人：

① 谦虚接受建议，立即改正，积极寻求解决方案。

② 逻辑清晰，回复内容详实、格式美观。

③ 用图片、表格等辅助说明，展示专业性和认真态度。

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参考资料：

[1] https://www.nature.com/articles/s41467-025-57309-4

[2] https://static-content.springer.com/esm/art%3A10.1038%2Fs41467-025-57309-4/MediaObjects/41467_2025_57309_MOESM2_ESM.pdf