CAR-T cells mainly rely on engineered CARs, exhibiting antigen specificity and T-cell cytotoxicity [
8]. The targets of hematological malignancies are concentrated on CD19, BCMA, CD20 and CD22. In addition, there are some other TAAs, CD23, CD30, CD33, SLAMF, ROR1, GRP78, CD138 etc. CD19, CD20, CD22, CD23 and ROR1 are usually used targets for B-cell malignancies [
36‐
40]. Among them, CD19 is the most frequently used target and highly expressed in most B-cell malignancies [
36]. CD30 is usually expressed on tumour cells of Hodgkin’s lymphoma [
41]. CD33 is a favorable target for leukemia, especially acute myeloid leukemia (AML) [
42]. SLAMF, BCMA and CD138 are developed to treat multiple myeloma (MM) [
43‐
45], especially BCMA. When CAR-T cells recognize specific TAAs [
8], ITAMs initiate activation via phosphorylation, promoting proliferation, releasing cytokines and boosting immune responses. However, this binding mechanism has certain limitations. Loss of expression of TAAs (such as CD19 or CD20) has been known as one of the key mechanisms of tumour resistance [
46]. Furthermore, not the same as tumour specific antigens (TSAs), TAAs have low selectivity, which are overexpressed on tumours, but also expressed on normal organs and tissues [
47], causing off-target effects and raising safety concern.
Cytotoxicity is usually exerted via; i. Cytokine secretion of granzyme and perforins by CAR-T cells [
48], which is the primary way to inhibit tumour progression and ii. Stimulation of cancer cell apoptosis by activating the apoptosis signaling pathway, including activation of the BH3-interacting domain death agonist (BID) and FAS-associated death domain protein (FADD) [
49,
50].