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\title{Efficacy and Mechanism of Combining Radiotherapy and Immunotherapy in
Stage IV NSCLC}



\author[1]{Mingyue Wang}%
\author[1]{Jing Sui}%
\author[1]{Shuo Li}%
\author[1]{ Shu-Jing Li}%
\author[2]{Ming-Xia Wang}%
\author[1]{Fang-Ling Ning}%
\author[1]{Li-Jun Tian}%
\affil[1]{Binzhou Medical College Affiliated Hospital}%
\affil[2]{Binzhou Medical University - Yantai Campus}%


\vspace{-1em}



  
  \date{May 07, 2026}


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\begin{CJK}{UTF8}{gbsn}放疗与免疫治疗联合治疗的疗效及机制 \end{CJK}\selectlanguage{english}IV\begin{CJK}{UTF8}{gbsn}期非小细胞肺癌

王明月\end{CJK}\selectlanguage{english}11\begin{CJK}{UTF8}{gbsn}第一作者\end{CJK}\selectlanguage{english},Bin Zhou Yi Ke Da Xue  Yi Yuan \selectlanguage{english}, Dian Zi You Jian \selectlanguage{english}: \selectlanguage{english}wmybjyx99@163.com,
\begin{CJK}{UTF8}{gbsn}隋静\end{CJK}\selectlanguage{english}, Li Shuo \selectlanguage{english}, Li Shu Jing \selectlanguage{english}, Wang Ming Xia \selectlanguage{english}, Zhu Fang Ling \selectlanguage{english}22\begin{CJK}{UTF8}{gbsn}通讯作者\end{CJK}\selectlanguage{english},
\selectlanguage{english}Email:ningfangling@126.com*, \begin{CJK}{UTF8}{gbsn}田立军\end{CJK}\selectlanguage{english}33\begin{CJK}{UTF8}{gbsn}对应 作者\end{CJK}\selectlanguage{english},
\selectlanguage{english}Email:byfyzlt@bzmc.edu.cn*

\begin{CJK}{UTF8}{gbsn}抽象

肺癌是全球癌症相关死亡的主要原因。
约\end{CJK}\selectlanguage{english}85\%\begin{CJK}{UTF8}{gbsn}的肺癌患者患有\end{CJK}\selectlanguage{english}NSCLC;\begin{CJK}{UTF8}{gbsn}大多数被诊断为 初次就诊时为 \end{CJK}\selectlanguage{english}IV
\begin{CJK}{UTF8}{gbsn}期疾病。随着连续 肿瘤学\end{CJK}\selectlanguage{english},Mian Yi Liao Fa Huo Mian Yi Hua Liao De Fa Zhan Yi Cheng Wei 
\selectlanguage{english}IV\begin{CJK}{UTF8}{gbsn}期\end{CJK}\selectlanguage{english}NSCLC\begin{CJK}{UTF8}{gbsn}患者的一线治疗。然而\end{CJK}\selectlanguage{english},[?] Ge  Huan Zhe Bi Li Reng Dui Zhi Liao Fang An Chan Sheng Nai Yao Xing 
Bing Jing Li Ju Bu Jin Zhan \selectlanguage{english},Yuan Fa Xing Fei Bu Bing Bian Jin Zhan  \selectlanguage{english}IV\begin{CJK}{UTF8}{gbsn}期\end{CJK}\selectlanguage{english}NSCLC\begin{CJK}{UTF8}{gbsn}的主要进展模式。临床前和临床
研究表明\end{CJK}\selectlanguage{english},Fang Liao Ke You Fa Quan Shen Xing  Kang Zhong Liu Mian Yi Fan Ying He Zhi Qian Jia Ju Bu Fang Liao 
Yan Zheng Jin Zhan Ke Yi Yan Chang Sheng Cun Qi . Yin Ci \selectlanguage{english},Wo Men Kao Lu Liao  Shi Fou Zai Fei Bu Jin Zhan Qian Jin Xing Ju Bu Fang Liao 
Jie Shou Mian Yi Zhi Liao Huo Mian Yi Zhi Liao De \selectlanguage{english}IV\begin{CJK}{UTF8}{gbsn}期\end{CJK}\selectlanguage{english}NSCLC\begin{CJK}{UTF8}{gbsn}患者的病变
化疗将是有益的。本次审查的重点是\end{CJK}\selectlanguage{english}: Fang Liao He Mian Yi Zhi Liao De Kang Zhong Liu Liao Xiao \selectlanguage{english},Qiang Diao 
Jia Fang Liao Shi Jian He Lian He Zhi Liao De An Quan Xing  Yong Yu  \selectlanguage{english}IV \begin{CJK}{UTF8}{gbsn}期 \end{CJK}\selectlanguage{english}NSCLC \begin{CJK}{UTF8}{gbsn}并了解潜在机制。

关键词\end{CJK}\selectlanguage{english}:\selectlanguage{english}IV\begin{CJK}{UTF8}{gbsn}期\end{CJK}\selectlanguage{english}NSCLC,\begin{CJK}{UTF8}{gbsn}联合治疗\end{CJK}\selectlanguage{english},Mian Yi Zhi Liao \selectlanguage{english}, Fang She Xian Liao Fa 

Jie Shao 

Fei Yan Shi Mu Qian Zui Duo De  Liu Xing De E Xing Zhong Liu He Yan Zheng Xiang Guan Si Wang De Zhu Yao Yuan Yin 
Quan Shi Jie Gu Ji You \selectlanguage{english}3\begin{CJK}{UTF8}{gbsn}万人死于 \end{CJK}\selectlanguage{english}1\textsuperscript{{[}1{]}}.\begin{CJK}{UTF8}{gbsn}在中国\end{CJK}\selectlanguage{english},Fei Yan De Fa Bing Lu 
Jin Nian Lai Xian Zhu Zeng Jia .  \selectlanguage{english}NSCLC\begin{CJK}{UTF8}{gbsn}占肺的\end{CJK}\selectlanguage{english}85\%
\begin{CJK}{UTF8}{gbsn}癌症;\end{CJK}\selectlanguage{english}IV\begin{CJK}{UTF8}{gbsn}期非小细胞肺癌\end{CJK}\selectlanguage{english}(\selectlanguage{english}NSCLC)\begin{CJK}{UTF8}{gbsn}是最常见的 \end{CJK}\selectlanguage{english}5\begin{CJK}{UTF8}{gbsn}年生存率低于\end{CJK}\selectlanguage{english}5\%\begin{CJK}{UTF8}{gbsn}的病理型\end{CJK}\selectlanguage{english},
Te Bie Shi Zai Chu Bu Zhen Duan Zhong \selectlanguage{english}\textsuperscript{{[}1-4{]}}.

\begin{CJK}{UTF8}{gbsn}正在进行的免疫疗法或免疫疗法结合的研究
化疗现在是\end{CJK}\selectlanguage{english}IV.\begin{CJK}{UTF8}{gbsn}期\end{CJK}\selectlanguage{english}NSCLC\begin{CJK}{UTF8}{gbsn}的一线治疗。几个
临床试验\end{CJK}\selectlanguage{english},Ru \selectlanguage{english}IMpower132\begin{CJK}{UTF8}{gbsn}试验\end{CJK}\selectlanguage{english}\textsuperscript{{[}5{]}}\begin{CJK}{UTF8}{gbsn}和主题演讲-\end{CJK}\selectlanguage{english}189\textsuperscript{{[}6{]}},\begin{CJK}{UTF8}{gbsn}已证明其益处
免疫治疗或 \end{CJK}\selectlanguage{english}IV \begin{CJK}{UTF8}{gbsn}期 \end{CJK}\selectlanguage{english}NSCLC \begin{CJK}{UTF8}{gbsn}患者的免疫化疗\end{CJK}\selectlanguage{english},You Qi Shi  Cheng Xu Xing Si Wang Pei Ti  \selectlanguage{english}1
\begin{CJK}{UTF8}{gbsn}的肿瘤比例评分患者 \end{CJK}\selectlanguage{english}(\selectlanguage{english}PD-L1) \begin{CJK}{UTF8}{gbsn}的 \end{CJK}\selectlanguage{english}50\% \begin{CJK}{UTF8}{gbsn}或更高。虽然大多数\end{CJK}\selectlanguage{english}IV\begin{CJK}{UTF8}{gbsn}期患者
\end{CJK}\selectlanguage{english}NSCLC------\begin{CJK}{UTF8}{gbsn}一线治疗 免疫疗法或免疫化疗------取得良好疗效\end{CJK}\selectlanguage{english},[?] Bu Fen 
De Huan Zhe Chu Xian Ji Bing Jin Zhan . Zhi De Zhu Yi De Shi You Duo Shao  Ji Bing Jin Zhan De Fang Shi . Qi Zhong \selectlanguage{english}, Jin Zhan Mo Shi 
Yi Zhi Fei Yan Shi Yuan Fa Xing Zhong Liu Kuo Da , Gua Zhuan Yi ,  He Yan Fan Zhuan Yi \selectlanguage{english}\textsuperscript{{[}7{]}}.
Xu\begin{CJK}{UTF8}{gbsn}等人研究了 接受免疫治疗至少 \end{CJK}\selectlanguage{english}3 \begin{CJK}{UTF8}{gbsn}次的 \end{CJK}\selectlanguage{english}IV \begin{CJK}{UTF8}{gbsn}期 \end{CJK}\selectlanguage{english}NSCLC
\begin{CJK}{UTF8}{gbsn}月份\end{CJK}\selectlanguage{english}\textsuperscript{{[}8{]}}. \begin{CJK}{UTF8}{gbsn}寡头进展\end{CJK}\selectlanguage{english}(\selectlanguage{english}55.3\%)\begin{CJK}{UTF8}{gbsn}是
免疫治疗耐药的主要模式。然而\end{CJK}\selectlanguage{english},Gua He Gan Suan Jin Zhan  Bi Jiao Yan Fan \selectlanguage{english},Bao Gua 
Zai Shao Yu Liang Ge Bing Zao Bu Wei Jin Zhan .  Ci Wai \selectlanguage{english},Yan Jiu Fa Xian \selectlanguage{english}, Yuan Fa Xing Zhong Liu Bing Bian Shi 
Fei Yan Jin Zhan De Zui Zhong Yao Bu Wei \selectlanguage{english}\textsuperscript{{[}9, 10{]}}.\begin{CJK}{UTF8}{gbsn}此外\end{CJK}\selectlanguage{english},Pu Nei Si Deng  Fa Xian 
\selectlanguage{english}70\% \begin{CJK}{UTF8}{gbsn}的 \end{CJK}\selectlanguage{english}IV \begin{CJK}{UTF8}{gbsn}期 \end{CJK}\selectlanguage{english}NSCLC \begin{CJK}{UTF8}{gbsn}患者接受 维持化疗在原发肺上进展
病变\end{CJK}\selectlanguage{english}\textsuperscript{{[}11{]}}.\begin{CJK}{UTF8}{gbsn}对于原发性病变进展\end{CJK}\selectlanguage{english},Zhe Xie 
Huan Zhe Ke Yi Cong Ju Bu Zhi Liao Zhong Shou Yi \selectlanguage{english}\textsuperscript{{[}12{]}}. \begin{CJK}{UTF8}{gbsn}放疗是
晚期肺癌。先前的研究表明\end{CJK}\selectlanguage{english}, Fang Liao Bu Jin Ke Yi Huan Jie Huan Zhe De Lin Chuang Zheng Zhuang 
You Xian De Zhuan Yi Xing \selectlanguage{english}NSCLC\begin{CJK}{UTF8}{gbsn}也延长了生存时间 病人\end{CJK}\selectlanguage{english}\textsuperscript{{[}11,
13{]}}.\begin{CJK}{UTF8}{gbsn}同样\end{CJK}\selectlanguage{english},Dan Ni Er \selectlanguage{ngerman}· \begin{CJK}{UTF8}{gbsn}调查了\end{CJK}\selectlanguage{english}IV\begin{CJK}{UTF8}{gbsn}期\end{CJK}\selectlanguage{english}NSCLC\begin{CJK}{UTF8}{gbsn}疾病进展前的治疗情况
接受一线治疗\end{CJK}\selectlanguage{english}\textsuperscript{{[}14{]}}.\begin{CJK}{UTF8}{gbsn}作者
发现添加局部\end{CJK}\selectlanguage{english}PFS(\begin{CJK}{UTF8}{gbsn}无进展生存期\end{CJK}\selectlanguage{english})Geng Gao  Zhi Liao Yu Wei Chi Zhi Liao \selectlanguage{english}(\selectlanguage{english}14.2\begin{CJK}{UTF8}{gbsn}个月 \end{CJK}\selectlanguage{english}vs
4.4\begin{CJK}{UTF8}{gbsn}个月\end{CJK}\selectlanguage{english}). Yin Ci  Zai Mian Yi Zhi Liao Huo Mian Yi Hua Liao Guo Cheng Zhong De Zhi Liao 
\selectlanguage{english}IV\begin{CJK}{UTF8}{gbsn}期\end{CJK}\selectlanguage{english}NSCLC\begin{CJK}{UTF8}{gbsn}患者\end{CJK}\selectlanguage{english},Jia Fa Neng Bu Neng You Geng Hao De Xiao Guo  Fei Jin Zhan Qian De Ju Bu Fang Liao \selectlanguage{english}?

Yin Ci \selectlanguage{english},Wo Men Zong Shu Liao Mian Yi Zhi Liao Lian He 
Fang Liao He Lin Chuang Shi Yan Zheng Ju \selectlanguage{english},Yi Tao Lun Dui Yi Xia Qing Kuang Xia De Fan Ying  Jie Shou Guo  \selectlanguage{english}IV \begin{CJK}{UTF8}{gbsn}期 \end{CJK}\selectlanguage{english}NSCLC
\begin{CJK}{UTF8}{gbsn}患者的放疗 免疫疗法或免疫化疗。

放疗联合免疫治疗的协同机制

临床前研究已经证明了协同效应和 放疗和免疫之间的相互作用。放射线疗法
可以通过调节肿瘤发挥抗肿瘤免疫作用
微\end{CJK}\selectlanguage{english}\textsuperscript{{[}15{]}}.\begin{CJK}{UTF8}{gbsn}同样\end{CJK}\selectlanguage{english},Mian Yi Liao Fa Ke Yi 
Ye Jian Shao Liao Fang She Zhi Liao De Que Dian \selectlanguage{english},Cong Er Zeng Qiang Liao  Kang Zhong Liu Zuo Yong . 

Fang Liao De Mian Yi Zuo Yong 

Fang Liao Ke Dao Zhi Zhong Liu Xi Bao Mian Yi Yuan Xing Xi Bao Si Wang \selectlanguage{english}(\selectlanguage{english}ICD) \begin{CJK}{UTF8}{gbsn}通过活性氧\end{CJK}\selectlanguage{english}(\selectlanguage{english}ROS)\begin{CJK}{UTF8}{gbsn}介导的\end{CJK}\selectlanguage{english}DNA
\begin{CJK}{UTF8}{gbsn}损伤\end{CJK}\selectlanguage{english}\textsuperscript{{[}16{]}}.ICD\begin{CJK}{UTF8}{gbsn}之后是释放 肿瘤相关抗原 \end{CJK}\selectlanguage{english}(\selectlanguage{english}TAA)
\begin{CJK}{UTF8}{gbsn}和内源性危险 信号损伤相关分子模式 \end{CJK}\selectlanguage{english}(\selectlanguage{english}DAMP),\begin{CJK}{UTF8}{gbsn}例如高 移动性组框 \end{CJK}\selectlanguage{english}1
(HMGB1)\begin{CJK}{UTF8}{gbsn}、三磷酸腺苷 \end{CJK}\selectlanguage{english}(\selectlanguage{english}ATP) \begin{CJK}{UTF8}{gbsn}和 钙网蛋白
\end{CJK}\selectlanguage{english}(\selectlanguage{english}CRT)\textsuperscript{{[}17-19{]}}.\begin{CJK}{UTF8}{gbsn}这些物质可以
与树突状细胞\end{CJK}\selectlanguage{english}(\selectlanguage{english}DC)\begin{CJK}{UTF8}{gbsn}的表面受体结合或被吞咽 通过发展中国家\end{CJK}\selectlanguage{english},Dao Zhi 
Se Wen \selectlanguage{english}\textsuperscript{{[}17, 20{]}}.\begin{CJK}{UTF8}{gbsn}然后\end{CJK}\selectlanguage{english},Ji Huo De  \selectlanguage{english}DC \begin{CJK}{UTF8}{gbsn}迁移到
附近的淋巴结\end{CJK}\selectlanguage{english},Jiang Kang Yuan Xin Xi Cheng Xian Gei \selectlanguage{english}T\begin{CJK}{UTF8}{gbsn}细胞\end{CJK}\selectlanguage{english},Cong Er  Cu Jin \selectlanguage{english}T\begin{CJK}{UTF8}{gbsn}细胞的活化和增殖\end{CJK}\selectlanguage{english},Fa Hui 
Mian Yi Diao Jie Zuo Yong . Zhe Ge Guo Cheng Chi Bu Kai  Zhu Yao Zu Zhi Xiang Rong Xing Fu He Ti  \selectlanguage{english}1 (MHC-I) \begin{CJK}{UTF8}{gbsn}分子的上调
和共刺激分子\end{CJK}\selectlanguage{english},Ru \selectlanguage{english}CD80\textsuperscript{{[}21{]}}.
\begin{CJK}{UTF8}{gbsn}最后\end{CJK}\selectlanguage{english},Huo Hua De \selectlanguage{english}T\begin{CJK}{UTF8}{gbsn}细胞实现对肿瘤细胞的归巢\end{CJK}\selectlanguage{english},Bing Fa Hui 
Kang Zhong Liu Mian Yi Zuo Yong . Ci Wai \selectlanguage{english},Shu Tu Zhuang Xi Bao \selectlanguage{english}(\selectlanguage{english}DC)\begin{CJK}{UTF8}{gbsn}也可以吸收
受损的细胞质\end{CJK}\selectlanguage{english}DNA\begin{CJK}{UTF8}{gbsn}并诱导\end{CJK}\selectlanguage{english}DC\begin{CJK}{UTF8}{gbsn}分泌干扰素\end{CJK}\selectlanguage{greek}β\selectlanguage{english}(\selectlanguage{english}IFN-\selectlanguage{greek}β\selectlanguage{english})
\begin{CJK}{UTF8}{gbsn}可以通过\end{CJK}\selectlanguage{english}GMP-AMP\begin{CJK}{UTF8}{gbsn}合成酶-干扰素基因杀死肿瘤细胞
刺激器\end{CJK}\selectlanguage{english}(\selectlanguage{english}cGAS-STING)\begin{CJK}{UTF8}{gbsn}通路\end{CJK}\selectlanguage{english}\textsuperscript{{[}22, 23{]}}.

II. IMMUNOTHERAPY ENHANCES THE EFFICACY OF RADIOTHERAPY

Studies have reported that not only radiotherapy has immune effects, but
immunotherapy also sensitizes radiotherapy, thus playing a synergistic
role. Previous research has suggested that radiotherapy does not produce
a durable anti-tumor effect, and it can induce an increase in regulatory
T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). These
cells can inhibit anti-tumor immune effects and reduce radiosensitivity
through transforming growth factor-\selectlanguage{greek}β \selectlanguage{english}(TGF-\selectlanguage{greek}β\selectlanguage{english}) and interleukin-10
(IL-10)\textsuperscript{{[}24, 25{]}}. Immunotherapy, such as the use of
PD-1/PD-L1 inhibitors, activates large numbers of CD8+T cells to induce
the expression of tumor necrosis factor-\selectlanguage{greek}α \selectlanguage{english}(TNF-\selectlanguage{greek}α\selectlanguage{english}), which in turn
suppresses the effect of regulatory T cells (Tregs) and myeloid-derived
suppressor cells (MDSCs), thereby weakening the resistance to
radiotherapy and producing a durable anti-tumor
effect\textsuperscript{{[}26{]}}.

Some preclinical studies have demonstrated that radiotherapy can
up-regulate the expression of PD-L1, mainly expressed on the surface of
tumor cells and antigen-presenting cells (APCs) via the JAK--STAT--IRF
and cGAS-STING pathways\textsuperscript{{[}27-29{]}}. PD-L1 can bind to
PD-1 on the surface of T cells, B cells, NK cells, and other
lymphocytes, thereby inhibiting the anti-tumor effect of CD8+T
lymphocytes\textsuperscript{{[}16, 30{]}}. Therefore, anti-PD-L1
inhibitors can consume part of PD-L1, thus weakening the anti-tumor
inhibition effect. Researchers have applied radiotherapy and
immunotherapy to mice and found that the expression levels of PD-L1 on
DC, tumor cells, and macrophages after radiotherapy were increased
compared with that of the same cell population in control tumor
cells\textsuperscript{{[}31{]}}. This inhibitory effect can be broken by
adding PD-1/PD-L1 inhibitors. Therefore, radiotherapy combined with
immunotherapy can play a synergistic and complementary anti-tumor role.
One experimental study observed improved survival in mice with combined
anti-PD-1 therapy and radiation compared with monotherapy, and only a
small percentage (15\%--40\%) of the animals in the combination group
survived more than 180 days after treatment. Immunological data revealed
that compared with monotherapy, cytotoxic T cells (CD8+/ IFN-\selectlanguage{greek}γ \selectlanguage{english}+/ TNF-\selectlanguage{greek}α
\selectlanguage{english}+) were increased, and regulatory T cells (CD4+/ FOXP3) were decreased
in the combined treatment group\textsuperscript{{[}21{]}}.

III. RELATIONSHIP BETWEEN TAMs AND IMMUNOLOGICAL COMBINED RADIOTHERAPY

Studies have demonstrated that radiotherapy can activate
tumor-associated macrophages (TAMs). TAMs include M1 macrophages and M2
macrophages. Notably, their effects on cancer are opposed. There is
evidence that M1 macrophages can play an anti-tumor role by
up-regulating the expression of TNF-\selectlanguage{greek}α \selectlanguage{english}and interleukin-6
(IL-6)\textsuperscript{{[}32{]}}. Nevertheless, M2 macrophages can
promote the expression of TGF-\selectlanguage{greek}β \selectlanguage{english}and epidermal growth factor (EGF) to
produce an immune suppressive effect, thereby promoting the growth and
metastasis of tumor cells\textsuperscript{{[}33{]}}.

Researchers believe that radiotherapy can increase the aggregation of
TAMs, especially M2 macrophages. Radiotherapy activates the STAT pathway
through the expression of colony-stimulating factor-1 (CFS-1),
activating M2 macrophages. The activated M2 macrophages recruit
regulatory T cells (Tregs) that inhibit anti-tumor activity, thereby
promoting tumor growth\textsuperscript{{[}34, 35{]}}. However, the
relationship between radiotherapy and TAMs is still being explored. Some
studies have suggested that the radiotherapy dose is related to the type
of TAMs. For example, low-dose radiotherapy can promote the activation
of M2 macrophages, whereas radiotherapy greater than 1 Gy promotes the
polarization of M1 macrophages\textsuperscript{{[}36{]}}.

By contrast, Cao et al. reported that PD-1/PD-L1 inhibitors can induce
the transformation of M2 TAMs into M1 TAMs\textsuperscript{{[}37{]}}.
There is evidence that PD-1/PD-L1 is associated with the polarization of
TAMs\textsuperscript{{[}38{]}}. Liu et al. found that PD-L1 was
significantly elevated in tumor and stromal compartment macrophages
compared to other immune cells\textsuperscript{{[}39{]}}. PD-1/PD-L1 is
highly expressed in TAMs and can induce polarization toward M2 TAMs by
transmitting negative regulatory signals and other mechanisms, which are
still being explored. In this case, the addition of PD-1/PD-L1 inhibitor
can reverse this effect; thereby, it can reduce the amount of M2 TAMs,
increase the amount of M1 TAMs, and induce the up-regulation of TNF-\selectlanguage{greek}α,
\selectlanguage{english}interleukin-12 (IL-12), and reactive oxygen species, which play an
essential role in T cell activation, thus making up for the deficiency
of radiotherapy and playing an anti-tumor
role\textsuperscript{{[}40-42{]}}. Furthermore, other specific
mechanisms of immunotherapy-induced polarization of M1 TAMs must be
investigated.

IV. ABSCOPAL EFFECTS OF RADIOTHERAPY

The abscopal effect, that is, radiotherapy, through its immunomodulatory
effect, can play an anti-tumor role at the site of the tumor radiation
field and induce adaptive immune response at the site of distant
metastasis without radiotherapy\textsuperscript{{[}43, 44{]}}. Although
the specific mechanism of the abscopal effect is not completely clear,
studies have proved that the abscopal effect exists. In the process of
radiation therapy, radiation can cause cancer cells to die and increase
blood flow, change the tumor microenvironment tumor antigen so that
activation of CD8 + T cells throughout the body through the blood
circulation, including unexposed sites, is beneficial to the immune
system and recognizes tumor cells, leading to reduction or disappearance
of distant metastatic sites \textsuperscript{{[}45, 46{]}}. In a mouse
model of anti-PD-1-resistant 344SQNSCLC adenocarcinoma, radiotherapy was
used to treat primary tumors, and a trend was found to increase M1 TAMs
in abdominal tumors\textsuperscript{{[}47{]}}. In another study on the
model of primary anti-PD-1 resistance, the combination of anti-PD-1 and
radiotherapy for primary tumors significantly reduced the growth of
primary tumors and significantly controlled tumors without radiotherapy
and reduced spontaneous lung metastasis (abscopal
effect)\textsuperscript{{[}48{]}}.

CURATIVE EFFECT

Recently, preclinical and clinical trials have demonstrated a prolonged
survival benefit of immunotherapy combined with radiotherapy in patients
with stage IV NSCLC.

Michel et al. found that adding NHS-IL2 immune cytokine and local
radiotherapy to first-line palliative chemotherapy reduced tumor size
and delayed tumor growth in a lung cancer animal
model\textsuperscript{{[}49{]}}. The NHS-IL2 consists of human NHS76
(antibody specific for necrotic DNA) fused to genetically modified human
interleukin-2 (IL-2). Furthermore, mice models of lung cancer treated
with low-dose radiotherapy (LDRT) and anti-PD-1 inhibitors achieved
better tumor control and prolonged survival\textsuperscript{{[}50{]}}.

The enhanced anti-tumor effects of immunotherapy combined with
radiotherapy have been confirmed in preclinical studies and demonstrated
in several clinical trials.

A study demonstrated a considerable benefit of local control and
survival by adding stereotactic radiotherapy (SBRT) in patients with
oligoprogression after required resistance to checkpoint inhibitors
(ICIs) in stage IV NSCLC \textsuperscript{{[}51{]}}. The trial enrolled
advanced NSCLC patients receiving at least two cycles of immunotherapy
and had minimal progression. The sites of oligometastases in these
patients included the lungs, brain, lymph nodes, adrenal glands, liver,
and cervical spine. Overall survival after oligoprogression (OS-PO) was
34 months in patients treated with immunotherapy combined with SBRT
versus 22 months in patients without SBRT. Many studies have found that
immunotherapy combined with radiotherapy has survival benefits, and the
radiotherapy site includes not only the primary tumor, such as the lung,
but also metastatic sites, such as the liver and brain. As mentioned
previously, the most common site of progression of lung cancer after
systemic therapy is the primary lung lesion. Therefore, we must explore
whether adding lung radiation before the progression of the primary
lesion can provide additional benefits or prevention.

The PEMBRO-RT Phase 2 randomized trial enrolled patients with metastatic
NSCLC who progressed after at least one chemotherapy
regimen\textsuperscript{{[}52{]}}. Enrolled patients were randomly
assigned using a 1:1 ratio to receive treatment with pembrolizumab after
SBRT to the site of lung lesions or lymph node metastases (experimental
arm) or without SBRT (control arm). The ORR (Overall-Response-Rate) at
12 weeks was 18\% in the control arm vs. 36\% in the experimental arm (P
= 0.07). Median PFS was 1.9 months vs. 6.6 months (P = 0.19), and median
OS (Overall-Survival) was 7.6 months vs. 15.9 months (P = 0.16).
Although the experimental arm did not meet the study's pre-defined
criteria, it showed an increase in ORR, median PFS, and OS and no
increase in toxicity in the SBRT group. Many clinical trials have
demonstrated the feasibility of radiotherapy for pulmonary lesions. Li
et al. performed a real-world analysis and also found that the median
PFS (9 months vs. 5 months) and median OS (30 months vs. 16 months) were
both higher with sintilimab plus radiotherapy for stage III or IV NSCLC
than with sintilimab alone\textsuperscript{{[}53{]}}. Notably, CRT was
performed in patients with positive margins or gross residual tumors
after surgery. Patients with isolated or local metastases received SBRT
or CRT, indicating that lung radiotherapy combined with immunotherapy
can improve survival. Regretfully, the study did not focus on the timing
of adding radiotherapy, such as before or after the onset of disease
progression. Similarly, Ratnayake et al. found that patients with stage
IV NSCLC treated with nivolumab and radiotherapy as second-line or
subsequent therapy had significantly better PFS compared with patients
who did not receive radiotherapy (2.8 months vs. 1.3 months, p = 0.02).
The study also found that prior or concurrent thoracic radiotherapy was
well tolerated and not associated with an increased incidence of
pneumonia\textsuperscript{{[}54{]}}.

Based on these trials, we verified that radiotherapy to the lung lesion
combined with immunotherapy prolonged survival among patients with stage
IV NSCLC. As studies have demonstrated that the site is most likely to
progress after systematic treatment is the primary site, we wanted to
explore the feasibility of adding local radiation to the lung before
disease progression to prevent disease progression. Michael et al. found
that patients with stable or regressed stage IV cancer after systemic
therapy had a longer 2-year OS rate with SBRT for metastatic disease
than with progressive disease (55\% vs. 15\%)\textsuperscript{{[}55{]}}.
Although our literature search was limited, it cannot be denied that
radiotherapy of the primary tumor before disease progression is
acceptable.

The most frequently used radiotherapy modality in the literature is
SBRT. Nevertheless, conventional radiotherapy is commonly used in our
actual clinical practice. Can the addition of conventional radiotherapy
bring some benefits? Taugner et al. conducted a real-world study of
stage III NSCLC and revealed that concurrent chemoradiotherapy followed
by the addition of a PD-L1 inhibitor resulted in higher rates of PFS
(60.0\% vs. 31.8\%) and OS (100.0\% vs. 70.5\%) at 12 months than
chemoradiotherapy alone\textsuperscript{{[}56{]}}. This study was
applied to conventional fractionated thoracic radiotherapy. Although the
patients in this trial were not stage IV patients, it suggests that
conventional radiation therapy combined with immunotherapy seems to have
unexpected benefits. Similarly, the PORT-C randomized trial demonstrated
a higher incidence of 3-year disease-free survival (DFS) with the
addition of conventional radiotherapy to postoperative adjuvant
chemotherapy than with no radiotherapy in patients with pIIIA-N2 NSCLC
(40.5\% vs. 32.7\%)\textsuperscript{{[}57{]}}.

Thus, we realized that despite their differences in sensitivity and
tumor cell death patterns, SBRT and conventional radiotherapy are both
essentially radiotherapy\textsuperscript{{[}16, 58, 59{]}}. Both SBRT
and conventional radiotherapy can induce cell morphology enlargement and
cytoskeletal recombination, causing cancer cells to recognize these
stimuli and alter gene expression and cell signals and thereby altering
the biological process and cell function of cancer cells; cell
morphology and cytoskeletal enlargement are found to be
dose-independent\textsuperscript{{[}60{]}}. Radiotherapy can target the
designated dose to the tumor lesion, whereas normal structures outside
the tumor receive less dose, minimizing toxic effects on adjacent normal
tissues\textsuperscript{{[}61{]}}. Radiotherapy can also benefit cancer
patients by relieving pain, possibly curing, preserving organ integrity,
and cost effectiveness\textsuperscript{{[}62{]}}. Radiotherapy,
including SBRT and conventional radiotherapy, contributes to local tumor
control and enhances anti-tumor immune
effects\textsuperscript{{[}63{]}}. The antitumor effects of these two
kinds of radiotherapy have also been verified in the following clinical
practice..

The MDACC trial found that pembrolizumab combined with radiotherapy had
a longer median PFS compared with pembrolizumab alone (9.1 vs. 5.1
months, p = 0.52) for stage IV NSCLC\textsuperscript{{[}64{]}}. In this
study, the ORR (10\% vs. 38\%, p = 0.11) and median PFS (6.8 vs. 20.8
months, p = 0.03) were increased in the SBRT group compared with the
conventional radiotherapy group, but the increases were not significant.
Therefore, we believe that conventional radiotherapy for lung lesions in
combination with immunotherapy can benefit stage IV patients. The same
holds for lung lesions before their development. However, most studies
involved in this aspect are SBRT, and a few studies have related to
conventional radiotherapy (added before primary lesions progression
combined with immunotherapy), which requires further research and
exploration.

SAFETY OF COMBINATION THERAPY:

As conventional radiotherapy combined with immunotherapy can benefit
patients with stage IV NSCLC, can the adverse effects (AEs) of
combination therapy be tolerated?

Adverse effects can occur with any anti-tumor therapy, so toxicity
should be considered in the choice of
treatment\textsuperscript{{[}43{]}}. The ETOPNICOLAS trial studied the
safety of nivolumab when added to chemoradiotherapy in patients with
stage III NSCLC\textsuperscript{{[}65{]}}. Adding nivolumab to
conventional radiotherapy was safe and tolerable, with a 23.5\%
incidence of [?] grade 3 pneumonia. Combination therapy is tolerated in
patients with stage III NSCLC and those with stage IV disease. A
secondary analysis of KEYNOTE-001 found that after a median follow-up of
32.5 months, there was an acceptable safety profile about previous
radiotherapy combined with Pembrolizumab for stage IV
patients\textsuperscript{{[}66{]}}. Although treatment-related pulmonary
toxicity occurred in 13\% of patients who received chest radiation,
compared with 1\% of patients who did not, there was no statistical
difference in grade 3 or higher toxicity between the two studies.
Similarly, William et al. also found that adding thoracic radiotherapy
to treating stage IV lung cancer with ICIs can increase toxic effects,
especially pulmonary toxicity. However, it is not conspicuous and can be
tolerated by patients (3.3\% vs. 4.1\%)\textsuperscript{{[}67{]}}.
Notably, a small percentage of patients who received a median dose of
40cGy of chest radiation during or after immunotherapy did not develop
symptomatic pneumonitis, compared with a median dose of 60 cGy for most
patients. Tian et al. found that it is safe to receive concurrent
treatment of lung lesions SBRT and ICIs, defined as ICIs received within
30 days after pulmonary SBRT\textsuperscript{{[}68{]}}. In this study,
although 10.7\% of SBRT+ICIs patients developed grade 3 or higher
pneumonia, compared with 0\% of SBRT patients (p\textless{}0.01), the
patients tolerated it. In addition, it was found that radiotherapy for
two lobes had a higher risk of pneumonia than that for a single lobe
(66.75\% vs. 7.55\%, P=0.028). Here, there seems to be a relationship
between the size of the radiotherapy site and toxicity. A toxicity
analysis of thoracic radiotherapy combining with immunotherapy found
that 3.8\% of patients receiving the combination developed grade 3
pneumonia\textsuperscript{{[}69{]}}. Among them, the incidence of grade
[?]3 pneumonia was slightly higher in patients treated with concurrent
ICIs and chest radiotherapy compared with sequential therapy (7.1\% vs.
3.9\%), but the difference was not significant (P = 0.014).
Unfortunately, the distinction between concurrent and sequential
treatment is not described here.

When exploring the toxicity of lung radiotherapy combined with
immunotherapy, we found that the dose of radiotherapy, the area of the
irradiated lung, and the time interval between the two treatments were
all related to the toxicity. However, we believed that adding
radiotherapy before progression could benefit the aforementioned
parameters, but we were unsure about the specific time. Therefore, this
present article next focuses on the relationship between the interval
time between radiotherapy, immunization, and toxicity.

The PACIFIC study found a slight increase in pulmonary toxicity (33.9\%
vs. 24.8\%) with durvalumab administered between 1 and 42 days after the
completion of thoracic radiotherapy\textsuperscript{{[}70{]}}. However,
the study did not compare conditions at other time points. Another
systematic analysis of real-world studies found rates of all grade
pneumonia of 35\% and grade [?]3 pneumonia of
6\%\textsuperscript{{[}2{]}}. By contrast, the interval between
radiotherapy and immunotherapy was at least 42 days in more than half of
the patients. The two studies used the same treatment regimen, but the
latter was a real-world systematic analysis. The incidence of pulmonary
toxicity was similar. Radiotherapy was added before lung disease
progression occurred in the two studies. Andrew et al. conducted a
multicenter study and found that local radiotherapy combined with
immunotherapy was acceptable\textsuperscript{{[}71{]}}. There were 66
patients (50\%) who had received radiotherapy before the start of
immunotherapy, with a time interval of 71 days between the two
treatments, and 56 patients (42\%) who started radiation within 14 days
of immunotherapy. Patients who received radiotherapy after immunotherapy
had an increase in grade 3-5 ir-AEs compared to another arm (8\% vs.
4\%), but the timing of the addition of radiotherapy was not distinctly
associated with grade 3 or higher toxicity (P = 0.45). Other studies
have also found that combining radiotherapy and immunization has a high
safety profile and tolerable toxicity. Similarly, Donata et al. found
that only 6\% and 8\% of patients receiving immunotherapy combined with
chest radiotherapy developed grade 2 pneumonia and grade 2 esophagitis,
respectively\textsuperscript{{[}72{]}}. In combination therapy, there
are inevitably overlapping toxicities, especially pneumonia. However,
concurrent (immunotherapy and radiotherapy were started within 1 month)
and sequential therapy (within \textgreater{} 1 month and [?]6 months)
were not significantly associated with lung toxicity in subgroup
analyses.

With the aforementioned studies, the toxicity of concurrent
immunotherapy and radiotherapy is similar to that of sequential therapy,
and there is no significant difference. What's more, we found that the
toxicity of radiotherapy combined with immunotherapy before lung disease
progression was tolerable. Nevertheless, we did not rule out that the
more the time of radiotherapy and immunotherapy coincide, the more
detrimental to patients. It makes sense for more studies to target
intervals exceeding 1 month. However, studies in this area are not
abundant, and we must further explore the specific time of adding
radiotherapy for patients with stage IV NSCLC.

CONCLUSION:

Most preclinical studies have demonstrated that radiotherapy can enhance
the anti-tumor immune response, and immunotherapy can also
synergistically promote the anti-tumor effect of radiotherapy. More
clinical studies have also demonstrated that radiotherapy combined with
immunotherapy, compared with other treatments alone, has a higher
survival benefit, and patients can tolerate its toxic effects. It is
also feasible to add local radiotherapy before lung disease progression.
It is believed that the same is true for conventional radiotherapy.
Although the published literature has limited data, conventional
radiotherapy combined with immunotherapy has great promise in treating
stage IV NSCLC before the progression of primary focus. However, there
are some limitations in the research, such as the few studies on
conventional radiotherapy combined with immunotherapy, the specific time
to add conventional radiotherapy, a dose of radiotherapy, and anti-tumor
predictors are also major challenges. With the continuous development of
medicine, more preclinical and clinical studies are urgently needed to
explore these issues and challenges before this protocol can be widely
used.

\textbf{Acknowledgements:}

We thank the ShanDong Provincial Medical Association (No.YXH2022ZX02028)
for its financial support.

\textbf{Ethical statement:}

Not applicable.

\textbf{Conflict of intrerest:}

The authors declare that they have no competing interests\emph{.}

\textbf{Data availability statement:}

Data sharing is not applicable to this article as no new data were
created or analyzed in this study.

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