Table 1.

Advantages and disadvantages of the different CAR designs. Key benefits and limitations across multiple CAR design strategies are summarised, indicating their therapeutic potential and clinical applications.

	Pros	Cons
DUAL CAR [43,44,45]	specific anti-tumour activity high persistence of CAR-T cells powerful cytokine production reduced “on-target/off-tumour” toxicity	clinical outcomes are unclear long patient follow-up lack of appropriate target antigens for some therapies (acute myeloid leukemia)
TANDEM CAR [34,46,47]	easier manufacturing procedures efficient protection against antigen escape increased safety and efficacy controllable mechanism reduced manufacturing costs reduced on-target/off-tumour toxicity persistence of cytotoxic activity with no significant exhaustion	manufacturing costs are reduced, but not disappeared reduced side effects, but not eliminated requiring both tumour antigens to function simultaneously
UNIVERSAL CAR [48,49,50,51,52,53,54,55,56]	leukapheresis is not required higher uniformity healthy T cells cheaper short manufacturing periods no limitation in cell sources prevention of GVHD by knocking out TCR	long-term follow-up limited penetration in tumour sites exhaustion side effects (CRS, on-target/off-tumour toxicity)
SUPRA CAR [57,58,59]	multi-targeted and programmable CAR high specificity for cancer cells targeting multiple antigens reduced tumour escape reduced relapse CRS controlled and reduced	required presence of more than one antigen complex manufacturing CRS is reduced but not absent
SYNNOTCH CAR [34,42,60,61,62,63,64]	flexible structure and higher accuracy in antigen recognition with respect to traditional CARs versatile applicability lower possibility of side effects production of cytokines possibility to be effective in solid tumours exhaustion is reduced more specific tumour killing	side effects are still present exhaustion can occur
TRUCKS [9,65,66,67]	TME conditioning via cytokines possibility to be effective against solid tumours more persistence in the tumour stroma	side effects still present no complete efficacy on solid tumours
PHYSIOLOGICAL CAR [34,68,69,70,71,72]	a ligand is used as an extracellular antigen-binding domain more potent cytotoxicity and less immunogenicity compared to conventional CARs high production of IFNg and cytokines programmable, effective, and specific	immunogenicity is only reduced cytotoxicity is not always effective