Table 1 Summary of studies on non-invasive biomarkers for tumor ICI therapy efficacy recently

Radiomic-based biomarker

18F-FDG PET/CT signature

NSCLC

Pre-treatment

Patients

99,47,48

18F-FDG PET/CT signatures pre-treatment identified patients benefiting from ICIs

AUC = 0.86, 0.83, 0.81

[21]

PD-L1 DLS

NSCLC

Pre-treatment

Patients

697

Combined with clinical data, DLS was capable of accurately predicting DCB, PFS, and OS in different cohorts

C-index = 0.70–0.87

[22]

rADC

Glioblastoma

Post-treatment

Patients

44

Patients with rADC ≥ 1.63 showed longer OS

HR = 0.41, P = 0.02

[23]

Radiomic score of tumor-infiltrating CD8 + T cells

Advanced solid tumors

Pre-treatment

Patients

137

Higher radiomic scores at baseline correlated to a higher proportion of patients with objective response or SD at 6 months and longer OS

P = 0.025, 0.013 for objective response and SD respectively

HR = 0.58, P = 0.0081 for OS

[24]

Maximum ⁸⁹Zr-labeled CD4 ratio (tumor to heart)

7 different tumor models

Pre-treatment

Mice

35

The ⁸⁹Zr-labeled CD4 ratio > 9 was associated with longer OS

P = 0.0018

[25]

⁶⁸ Ga-grazytracer

Colon Cancer

12 days post-tumor inoculation

Mice

12

The high ⁶⁸ Ga-grazytracer uptake group showed smaller tumor volumes compared with the low uptake group

P < 0.05

[26]

SUVmax of ⁸⁹Zr-labeled atezolizumab

Bladder cancer, NSCLC, and TNBC

Pre-treatment

Patients

22

Patients with CR had a higher SUVmax compared to those with progressive disease

The geometric mean SUVmax correlated to PFS and OS

P = 0.00021

HR = 11.7, P = 0.000028 for PFS; HR = 6.3, P = 0.0027 for OS

[27]

⁸⁹Zr-labeled pembrolizumab

Advanced melanoma or NSCLC

Pre-treatment

Patients

18

The tumor SUVmax was associated with ICI response, PFS, and OS

P trend = 0.014

P = 0.0025 for PFS

P = 0.026 for OS

[28]

Blood-based biomarker

CTCs

NSCLC

Pre- and 4 weeks post-treatment

Patients

104

The presence of CTCs independently predicted the lack of durable response to ICIs at baseline and 4 weeks after treatment

OR 0.28, P = 0.02 at baseline; OR 0.07, P < 0.01 at four weeks after treatment

[29]

CTC heterogeneity

Metastatic genitourinary cancer

Pre- and on-treatment

Patients

81

The B and D subtypes were associated with shorter OS at baseline and on C2D1.baseline Increasing CTC heterogeneity correlated to worse OS during the treatment

P < 0.0001–0.013

P = 0.045

[30]

PD-L1 expression on CTCs

Metastatic melanoma

Pre-treatment

Patients

25

Patients with PD-L1 + CTCs had longer PFS

PD-L1 + CTCs were independent predictors of PFS

PFS, 26.6 vs. 5.5 months, P = 0.018

HR = 0.229, P = 0.026

[31]

PD-L1 expression on CTCs

NSCLC

8 weeks post-treatment

Patients

45

Patients with PD-L1 positivity rates ≥ 7.7% at week 8 had longer PFS

P < 0.01

[32]

Ki67 level of circulating PD-1 + CD8 + T cells

Melanoma

Pre- and 6 weeks post-treatment

Patients

29

Higher Ki67 levels of circulating PD-1 + CD8 + T cells at baseline showed worse OS

Patients with the ratio (PD-1 + Ki67 + CD8 + T cell to tumor burden) > 1.94 at 6 weeks post-treatment showed better outcomes in overall response rate, PFS, and OS

P = 0.02

P < 0.05

[33]

TCR diversity and clonality of PD1 + CD8 + T cells

NSCLC

Pre- and post-treatment

Patients

25, 15

Patients with higher TCR diversity pre-ICI had better responses and longer PFS in the combined dataset

Patients with increased TCR clonality post-ICI had longer PFS and OS

The optimal Youden’s index = 0.81, Sensitivity = 0.87, Specificity = 0.94 PFS, HR = 0.28; 95% CI 0.11–0.74, P = 0.002 OS, HR = 0.23, 95% CI 0.07–0.79; P = 0.034

[34]

TMR

NSCLC

Pre- and post-treatment

Patients

34

TMR could distinguish responders and non-responders

Patients with TMR > 0.39 had longer PFS

AUC = 87%

Median PFS, 103 vs. 35 days, P = 0.0079

[35]

LIPS

Multiple recurrent or metastatic cancer types

Pre-treatment and after the first application

Patients

56, 33

The signature predicted OS benefit accurately

The low-risk group had longer OS in the training and validation cohort

C index 0.74 vs. 0.71

Training cohort, HR = 0.26, 95% CI 0.12–0.56, P = 0.00025; Validation cohort, HR = 0.30, 95% CI 0.10–0.91, P = 0.024

[36]

ctDNA

NSCLC, Melanoma, Colorectal Cancer

8 weeks post-treatment

Patients

15

Detection of ctDNA at week 8 correlated with shorter PFS and OS

Median PFS, 11 vs. 2 months, HR 10.2, P = 0.001

OS, HR = 15, P = 0.004

[37]

bTMB

NSCLC

Pre-treatment

Patients

152

The bTMB-high group reached higher ORR values and longer OS

ORR, 35.7% vs. 5.5%, P < 0.0001

OS, 23.9 vs. 13.4 months, HR = 0.66, P = 0.18

[38]

bTMB

NSCLC

Pre-treatment

Patients

50

bTMB levels ≥ 6 was associated with better PFS and ORR

PFS, HR = 0.39, P = 0.01

ORR, 39.3% vs. 9.1%, P = 0.02

[39]

GIN

18 cancer types

6 weeks post-treatment

Patients

44

GIN of cfDNA depicted the ICI efficacy at week 6

HR (NRs vs. Rs) = 5.74, P = 0.001

[40]

Specific open regions of chromatin

Gastric cancer

Pre-treatment

Patients

32, 52

Patients with high chromatin openness tended to respond to ICIs and had better prognoses

Discovery cohort, Sensitivity 100.0%, Specificity 90.9%, P < 0.001

Validation cohort, Sensitivity 88.9%, Specificity 58.8%, P < 0.001

AUC = 0.717

[41]

Lung dynamics index

NSCLC

Pre- and within 4 weeks post-treatment

Patients

22

The index differentiated patients with DCB from NDB and correlated with PFS

AUC = 0.93

PFS, HR = 11.38, Wald P = 0.006

[42]

LIF

Multiple unresectable or metastatic cancer types

Pre-treatment

Patients

95, 292

The LIF-low group had longer PFS, OS, and DCB

Median PFS, 7.4 vs. 1.7 months, 95% CI 2.9–11.9 vs. 1.3–2.1 months, P < 0.0001

Median OS, 21.7 vs. 4.3 months, 95% CI 12‒31.4 vs. 3.4–5.1 months, P < 0.0001

DCB, 41.7% vs. 6.4%, P < 0.0001

AUC = 0.622

[43]

HIC

NSCLC

Pre-treatment

Patients

284, 877

The HIC-H group had longer OS in all ICI regimens and ICI monotherapy

Median OS, not-reached vs. 5.0 months, HR = 0.38, P < 0.0001 for all ICI regimens

OS, 16.8 vs. 2.8 months, HR = 0.36, P < 0.0001 for ICI monotherapy

[44]

CRAFITY score

HCC

Pre-treatment

Patients

190, 102

Patients with a low CRAFITY score had the longest OS and best radiological responses

P < 0.001, C index = 0.62

[45]

Circulating exosomal PD-L1

Melanoma

Pre- and 3–6 weeks post-treatment

Patients

39

High levels of circulating exosomal PD-L1 pre-treatment were associated with poor clinical outcomes

Responders showed increased exosomal PD-L1 levels at week 3–6

Patients with the fold change value > 2.43 at week 3–6 had better prognoses

P = 0.0018

P = 0.00001

P < 0.05

[46]

Circulating exosomal CD73

Melanoma

4 weeks post-treatment

Patients

41

Circulating exosomal CD73 greatly increased in non-responders at week 4 compared with baseline

P = 0.0041

[47]

EV-score

Gastric cancer

Pre- and at the first month post-treatment

Patients

112

Baseline EV-score could characterize 6-month PD or death

EV-score changes at the first month after treatment could predict prognosis

AUC = 0.729, 0.630

PFS, HR = 0.3677, P = 0.0471

OS, HR = 0.4568, P = 0.1828

[48]

Microbial biomarker

Microbiota composition

Cutaneous melanoma

Pre-treatment

Patients

94, 5 microbiome datasets

Baseline microbiota composition correlated to the outcome one year after ICI initiation in a cohort of 94 patients

Optimized algorithms predicted outcomes across five cohorts consistently

P = 0.006

AUC = 0.54–1.00

[49]

SCFA

Metastatic or advanced solid tumors

Pre-treatment

Patients

52

Responders had higher levels of fecal and serum SCFAs

P < 0.05

[50]

SCFA

Multiple myeloma

Pre-treatment

Patients

85

Lower baseline levels of butyrate and propionate were associated with longer PFS

P = 0.0015; P = 0.0029

[51]

Exhaled breath

Molecular profiles

NSCLC

Pre-treatment

Patients

92, 51

Baseline data significantly differentiated different responses at 3 months

AUC = 0.89, 0.85

[52]

SpiroNose exhaled breath data

NSCLC

6 weeks post-treatment

Patients

62, 32

The eNose was capable of distinguishing objective responders in the early stage

Training, AUC = 0.95, Sensitivity = 100%, Specificity = 73%Validation, AUC = 0.97

[53]

Other characteristics

Gender

Advanced or metastatic tumors

-

Patients

11,351

Men and women had different ICI outcomes

P = 0.0019

[54]

BMI

Melanoma

-

Patients

207, 331

Obese patients had improved PFS and OS in the immunotherapy cohort

HR = 0.75, 0.64

[55]

BMI

Melanoma

-

Patients

423

To observe the association between BMI and survival outcomes

NS

[56]

Body composition

Melanoma

-

Patients

287

Patients featured with sarcopenic obesity showed inferior PFS and those featured with high total adipose tissue index had shorter PFS

HR = 1.4, P = 0.04;

HR = 1.7, P = 0.04

[57]