Table 1.

Therapeutic strategies to combat tumor heterogeneity. ICB = Immune checkpoint blockade, OV = oncolytic virus, ACT = adoptive T cell transfer, OVV = oncolytic virus vaccine, HDACi = class I histone deacetylase inhibitor, CDK7 = cyclin-dependent kinase 7, RCC = renal cell carcinoma.

Approach	Rationale	Examples
Combination Therapies	Using a multi-pronged approach to target multiple pathways simultaneously, preventing selection of resistant populations	1. Chemotherapy + ICB improves progression-free survival in patients [58,59,61,62] 2. Chemotherapy + OV improved therapeutic efficacy [63,64,65] 3. Chemotherapy + cell-based therapies [66,67,68] 4. ACT + OVV + HDACi reprogrammed immunosuppressive myeloid cells, eliminating antigen-negative tumor cells in mice [60] 5. CDK7 + ICB enhanced antitumor immunity and prolonged survival outcomes in mice [69]
Multi-Peptide Vaccines	Designed to create a response against several tumor antigens simultaneously	1. Multi-antigen vaccine in RCC patients increased the breadth of the immune response and resulted in better disease control [72] 2. Immunogenic neoantigens were first identified and then used to design multi-antigen vaccines, improving therapeutic outcomes [73,74]
Antigen Spread	Intended to enhance the T-cell repertoire, allowing for expansion of the immune response from a dominant antigen to secondary antigens	1. Autologous DCs pulsed with an immunodominant epitope resulted in antigen spread in one patient, resulting in a complete response to treatment [77] 2. Radiation therapy can expand T-cell repertoire, allowing for improved survival when combined with ICB [82]